NM_000527.5(LDLR):c.1775G>A (p.Gly592Glu) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PS4, PP1_Strong, PM2, PS3_Moderate, PP3 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PS4 - Variant meets PM2. Variant identified in 239 index cases. PP1_strong - 130 informative meioses (1 from Robarts Research Institute; 83 from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); 19 from Laboratory of Genetics and Molecular Cardiology; 2 from University of British Columbia; 25 from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge). PM2 - PopMax MAF = 0.0001161 (0.012%) in European non-Finnish exomes (gnomAD v2.1.1). PS3_moderate - Level 2 assay - PMID:21865347 - study on hmz patient's lymphocytes, FACS, LDLR activity value range: 39-53%. PP3 - REVEL: 0,938. PP4 - Variant meets PM2. Variant identified in 239 index cases fulfill specific clinical criteria for FH (3 cases with Simon-Broome from Color laboratory; 189 cases with MedPed criteria from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); 5 cases with Simon-Broome criteria from GeneDx; 15 cases with Siom-Broome criteria from Laboratory of Genetics and Molecular Cardiology; 2 cases with DLCN criteria from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA); 6 cases with DLCN criteria from University of British Columbia; 19 cases with Simon-Broome criteria from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge).
NM_000527.5(LDLR):c.1775G>A (p.Gly592Glu)
Germline
Reviewed by expert panel
Help
Reviewed by expert panel. Learn more about how ClinVar calculates review status.
Pathogenic
for
Hypercholesterolemia, familial, 1
Classification is based on the expert panel submission
Jun 2021 by
ClinGen Familial Hypercholesterolemia Variant Curation Expe…
Help
FDA Recognized Database
The classification is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000527.5(LDLR):c.1775G>A (p.Gly592Glu)
Variation ID: 161271 Accession: VCV000161271.101
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 19p13.2 19: 11116928 (GRCh38) [ NCBI UCSC ] 19: 11227604 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Dec 7, 2014 Jun 27, 2026 Jun 9, 2021 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000527.5:c.1775G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000518.1:p.Gly592Glu missense NM_001195798.2:c.1775G>A NP_001182727.1:p.Gly592Glu missense NM_001195799.2:c.1652G>A NP_001182728.1:p.Gly551Glu missense NM_001195800.2:c.1271G>A NP_001182729.1:p.Gly424Glu missense NM_001195803.2:c.1394G>A NP_001182732.1:p.Gly465Glu missense NC_000019.10:g.11116928G>A NC_000019.9:g.11227604G>A NG_009060.1:g.32548G>A LRG_274:g.32548G>A LRG_274t1:c.1775G>A LRG_274p1:p.Gly592Glu P01130:p.Gly592Glu - Protein change
- G592E, G424E, G465E, G551E
- Other names
-
FH Sicily
FH Foggia-1
FH Naples4
FH Sicilia-4
NP_000518.1:p.G592E
NM_000527.5(LDLR):c.1775G>A
- Canonical SPDI
- NC_000019.10:11116927:G:A
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD), exomes 0.00005
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00023
The Genome Aggregation Database (gnomAD) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00003
Exome Aggregation Consortium (ExAC) 0.00005
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| LDLR | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
4568 | 4909 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (28) |
reviewed by expert panel
|
Jun 9, 2021 | RCV000172964.54 | |
| Pathogenic (11) |
criteria provided, multiple submitters, no conflicts
|
Apr 27, 2026 | RCV000162001.51 | |
| Pathogenic/Likely pathogenic (7) |
criteria provided, multiple submitters, no conflicts
|
Jan 31, 2026 | RCV000587007.30 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Sep 4, 2020 | RCV000844730.13 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jun 1, 2014 | RCV002051664.12 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Dec 3, 2024 | RCV002399517.10 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
- | RCV003330084.3 | |
|
See cases
|
Pathogenic (1) |
criteria provided, single submitter
|
Dec 15, 2021 | RCV004584355.3 |
| Pathogenic (1) |
criteria provided, single submitter
|
Jun 17, 2022 | RCV005403770.1 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
Expand all rows
Collapse all rows
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Jun 09, 2021)
C
Contributing to aggregate classification
|
reviewed by expert panel
|
Hypercholesterolemia, familial, 1
(Semidominant inheritance)
|
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel
FDA Recognized Database
Accession: SCV001960930.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
Comment:
show
NM_000527.5(LDLR):c.1775G>A (p.Gly592Glu) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PS4, PP1_Strong, PM2, PS3_Moderate, PP3 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PS4 - Variant meets PM2. Variant identified in 239 index cases. PP1_strong - 130 informative meioses (1 from Robarts Research Institute; 83 from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); 19 from Laboratory of Genetics and Molecular Cardiology; 2 from University of British Columbia; 25 from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge). PM2 - PopMax MAF = 0.0001161 (0.012%) in European non-Finnish exomes (gnomAD v2.1.1). PS3_moderate - Level 2 assay - PMID:21865347 - study on hmz patient's lymphocytes, FACS, LDLR activity value range: 39-53%. PP3 - REVEL: 0,938. PP4 - Variant meets PM2. Variant identified in 239 index cases fulfill specific clinical criteria for FH (3 cases with Simon-Broome from Color laboratory; 189 cases with MedPed criteria from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); 5 cases with Simon-Broome criteria from GeneDx; 15 cases with Siom-Broome criteria from Laboratory of Genetics and Molecular Cardiology; 2 cases with DLCN criteria from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA); 6 cases with DLCN criteria from University of British Columbia; 19 cases with Simon-Broome criteria from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge). (less)
Observation: 1
Collection method: curation
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: curation
Allele origin: germline
Affected status: unknown
|
|
|
Likely pathogenic
(Mar 25, 2016)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Familial hypercholesterolemia
(Autosomal dominant inheritance)
|
LDLR-LOVD, British Heart Foundation
Accession: SCV000295649.2
First in ClinVar: Jul 29, 2016 Last updated: Mar 31, 2019 |
Observation:
12
Observation 1
Collection method: literature only
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
Observation 2
Collection method: literature only
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
Observation 3
Collection method: literature only
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
Observation 4
Collection method: literature only
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
Observation 5
Collection method: literature only
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
Observation 6
Collection method: literature only
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
Observation 7
Collection method: literature only
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
Observation 8
Collection method: literature only
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
Observation 9
Collection method: literature only
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
Observation 10
Collection method: literature only
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
Observation 11
Collection method: literature only
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
Observation 12
Collection method: literature only
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Sep 13, 2016)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Familial hypercholesterolemia |
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000697209.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
show
Variant summary: The LDLR c.1775G>A (p.Gly592Glu) variant involves the alteration of a conserved nucleotide. Gly592 is highly conserved across species, and 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 6/121608 control chromosomes at a frequency of 0.0000493, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0025031). This variant has been reported in many FH patients in both heterozygous, compound heterozygous, and homozygous states with evidence of co-segregation in some of the families. Functional studies indicate that the variant of interest has defective LDL receptor activity. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic/likely pathogenic. Taken together, this variant is classified as pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Sep 04, 2020)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Homozygous familial hypercholesterolemia
(Autosomal dominant inheritance)
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000271385.4
First in ClinVar: May 29, 2016 Last updated: May 29, 2021 |
Comment:
show
The p.Gly592Glu variant in LDLR has been reported in >200 Caucasian individuals with familial hypercholesterolemia (FH) and segregated with disease in >30 affected relatives from >3 families (Gorski 1998 PMID: 9654205, Miltiadous 2001 PMID: 11317361, Kuhrova 2002 PMID: 11754108, Kublaska 2008 PMID: 18263977, Bourbon 2008 PMID: 17765246, Chmara 2010 PMID: 20145306, Diakou 2011 PMID: 21925044, Tichy 2012 PMID: 22698793, Bertolini 2013 PMID: 23375686, Do 2015 PMID: 25487149, Medeiros 2015 PMID: 26020417, Jannes 2015 PMID: 25461735, Braenne 2015 PMID: 26036859). This variant has also been identified in 0.01% (15/129176) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with the frequency of FH in the general population. Furthermore, in vitro functional studies support that the p.Gly592Glu variant may impact protein function (Romano 2011 PMID: 21865347). In summary, this variant meets criteria to be classified as pathogenic for familial hypercholesterolemia in an autosomal dominant manner based upon presence in multiple affected individuals and segregation studies. ACMG/AMP Criteria applied: PS4, PP1_Strong, PS3_Supporting. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Number of individuals with the variant: 12
|
|
|
Pathogenic
(Dec 29, 2021)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Hypercholesterolemia, familial, 1 |
Baylor Genetics
Accession: SCV003836115.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
|
|
Pathogenic
(Mar 19, 2023)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
GeneDx
Accession: SCV000582282.9
First in ClinVar: Feb 28, 2015 Last updated: Apr 09, 2023 |
Comment:
show
Published functional studies demonstrate that G592E results in reduced LDL receptor activity (Hobbs et al., 1992); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as p.G571E, FH Sicily, FH Foggi, FH Naples-4; This variant is associated with the following publications: (PMID: 27998977, 11524740, 24627126, 25282520, 34167030, 32423031, 35339733, 34697415, 21310417, 15864114, 26238499, 11641914, 22390909, 25637381, 21865347, 20145306, 26036859, 20663204, 15523646, 11848618, 26666465, 27824480, 21382890, 27050191, 19062533, 27578104, 25463123, 27784735, 22294733, 22698793, 26020417, 26892515, 15890894, 23833242, 18263977, 25487149, 16627557, 25936317, 23375686, 24507775, 26723464, 28965616, 15241806, 19026292, 17539906, 9654205, 17196209, 11139254, 20506408, 11754108, 11317361, 31617323, 31447099, 21925044, 33975813, 33303402, 32719484, 32660911, 33269076, 32770674, 32977124, 31589614, 32041611, 33740630, 33418990, 34037665, 34456049, 32009526, 35741760, 35913489, 33955087, 30710474, 1301956) (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Likely pathogenic
(-)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Syndromic X-linked intellectual disability Najm type
(X-linked dominant inheritance)
|
Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin
Accession: SCV004037152.1
First in ClinVar: Sep 30, 2023 Last updated: Sep 30, 2023 |
Observation 1
Collection method: not provided
Allele origin: germline
Affected status: yes
Clinical Features:
Symptomatic seizures (present) , Microcephaly (present) , Cerebral atrophy (present) , Pontocerebellar atrophy (present) , Exotropia (present) , Global developmental delay (present) , Hearing impairment (present) , X-linked dominant inheritance (present)
|
|
|
Pathogenic
(Apr 08, 2022)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000888163.4
First in ClinVar: Feb 28, 2015 Last updated: Jan 06, 2024 |
Comment:
show
Internal analysis revealed that the variant was statistically enriched in familial hypercholesterolemia cases over matched controls in the published literature (PMID: 17765246 (2008), 20145306 (2010), 21925044 (2011), 22698793 (2012), and 23375686 (2013)). Additionally, reduced LDL receptor activity was observed from fibroblasts and peripheral blood T-lymphocytes extracted from patients with this variant ((PMID: 1301956 (1992) and 21865347 (2011)). (less)
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
|
|
Pathogenic
(Oct 08, 2024)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV005877212.1
First in ClinVar: Mar 11, 2025 Last updated: Mar 11, 2025 |
Comment:
show
The LDLR c.1775G>A; p.Gly592Glu variant (rs137929307), also published as Gly571Glu, FH Sicily, FH Foggia 1, and FH Naples 4, is reported in the literature in numerous heterozygous, homozygous, and compound heterozygous individuals affected with hypercholesterolemia and has been reported to segregate with disease in families (Bertolini 2020, Bertolini 2013, Braenne 2016, Hobbs 1992, Meshkov 2021, Wong 2019). This variant is found in the non-Finnish European population with an allele frequency of 0.01% (15/129,176 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses predict that this variant is deleterious (REVEL: 0.938), and functional analyses indicate reduced residual activity of the variant protein (Romano 2011). Based on available information, this variant is considered to be pathogenic. References: Bertolini S et al. Homozygous familial hypercholesterolemia in Italy: Clinical and molecular features. Atherosclerosis. 2020 Nov;312:72-78. PMID: 32977124. Bertolini S et al. Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy. Atherosclerosis. 2013 Apr;227(2):342-8. PMID: 23375686. Braenne I et al. Systematic analysis of variants related to familial hypercholesterolemia in families with premature myocardial infarction. Eur J Hum Genet. 2016 Feb;24(2):191-7. PMID: 26036859. Hobbs et al. Molecular genetics of the LDL receptor gene in familial hypercholesterolemia. Hum Mutat. 1992;1(6):445-66. PMID: 1301956. Meshkov A et al. The LDLR, APOB, and PCSK9 Variants of Index Patients with Familial Hypercholesterolemia in Russia. Genes (Basel). 2021 Jan 6;12(1):66. PMID: 33418990. Romano M et al. An improved method on stimulated T-lymphocytes to functionally characterize novel and known LDLR mutations. J Lipid Res. 2011 Nov;52(11):2095-100. PMID: 21865347. Wong KHY et al. Three patients with homozygous familial hypercholesterolemia: Genomic sequencing and kindred analysis. Mol Genet Genomic Med. 2019 Dec;7(12):e1007. PMID: 31617323. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Aug 26, 2022)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Hypercholesterolemia, familial, 1 |
MGZ Medical Genetics Center
Accession: SCV002580733.2
First in ClinVar: Oct 15, 2022 Last updated: Apr 13, 2025
Comment:
ACMG criteria applied: PS4, PP1_STR, PS3_MOD, PM2_SUP, PP3, PP4
|
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 5
Sex: male
|
|
|
Pathogenic
(Jun 17, 2022)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Dyslipidemia |
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV006065267.1
First in ClinVar: May 03, 2025 Last updated: May 03, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Mar 27, 2020)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Familial hypercholesterolemia |
Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service
Accession: SCV006306792.1
First in ClinVar: Aug 16, 2025 Last updated: Aug 16, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
Clinical Features:
Hyperlipidemia (present) , Hypercholesterolemia (present) , Hyperlipoproteinemia (present) , Elevated circulating LDL-C concentration (present)
|
|
|
Pathogenic
(Jan 22, 2026)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Hypercholesterolemia, familial, 1
(Semidominant inheritance)
|
Variantyx, Inc.
Accession: SCV007595407.1
First in ClinVar: May 16, 2026 Last updated: May 16, 2026 |
Comment:
show
This is a nonsynonymous variant in the LDLR gene (OMIM: 606945). Pathogenic variants in this gene have been associated with autosomal semidominant familial hypercholesterolemia 1. This variant has been reported in many unrelated affected individuals (PS4), and it has been observed to segregate with disease in many families in these reports (PP1) (reports include PMID: 20145306, 20663204, 21310417, 21925044, 22698793, 23375686, 25461735, 25463123, 25487149, 26020417, 26238499). The clinical symptoms reported for these individuals are highly specific for autosomal semidominant familial hypercholesterolemia 1, which has a limited genetic etiology (PP4). This variant Functional studies have shown that this variant alters LDLR protein function (PMID: 21865347) (PS3_Moderate), and multiple computational algorithms predict a deleterious effect for this variant (REVEL score: 0.938) (PP3). This variant has a 0.0060% maximum allele frequency in non-founder control populations (https://gnomad.broadinstitute.org/) (PM2). Other reputable laboratories have reported this variant as pathogenic or likely pathogenic, and this classification has been validated by an expert panel in ClinVar (PP5). Based on the current evidence, this variant is classified as pathogenic for autosomal semidominant familial hypercholesterolemia 1. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Nov 21, 2023)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Hypercholesterolemia, familial, 1 |
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital
Accession: SCV000268637.2
First in ClinVar: May 21, 2016 Last updated: Jun 27, 2026 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Likely pathogenic
(-)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Familial Hypercholesterolemia
(Autosomal dominant inheritance)
|
Institute for Integrative and Experimental Genomics, University of Luebeck
Accession: SCV000212140.1
First in ClinVar: Jun 20, 2015 Last updated: Jun 20, 2015 |
Observation: 1
Collection method: research
Allele origin: germline
Affected status: yes
Observation 1
Collection method: research
Allele origin: germline
Affected status: yes
|
|
|
Likely pathogenic
(Mar 01, 2016)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Familial hypercholesterolemia
(Autosomal dominant inheritance)
|
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge
Accession: SCV000322975.1
First in ClinVar: Oct 15, 2016 Last updated: Oct 15, 2016 |
Observation:
2
Observation 1
Collection method: research
Allele origin: germline
Affected status: yes
Comment on evidence:
%MAF (ExAC):0.004942
Observation 2
Collection method: research
Allele origin: germline
Affected status: yes
Comment on evidence:
Compound Heterozygous (with p.(Cys89Arg) or with p.(Pro685Leu)) patients' fibroblasts, 125I-LDL assays; Heterologous cells (CHO), FACS assays; Heterozygous patients' Epstein-Barr virus transformed lymphocytes, FACS assays
Result:
2-5% LDLR activity / 50% LDLR activity / 35-75% LDLR activity
|
|
|
Likely pathogenic
(-)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Hypercholesterolemia, familial, 1
(Autosomal dominant inheritance)
|
Robarts Research Institute, Western University
Accession: SCV000484718.1
First in ClinVar: Dec 17, 2016 Last updated: Dec 17, 2016 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 4
Zygosity: 1 Homozygote
|
|
|
Likely pathogenic
(Dec 16, 2016)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Hypercholesterolemia, familial, 1 |
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix
Accession: SCV000503412.1
First in ClinVar: Dec 17, 2016 Last updated: Dec 17, 2016 |
Comment:
show
subjects mutated among 2600 FH index cases screened = 11 , family members = 3 with co-segregation / previously described in association with FH, 5 to 15% LDLR Activity/software prediction damaging (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 11
|
|
|
Likely pathogenic
(Mar 01, 2016)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Familial hypercholesterolemia
(Autosomal dominant inheritance)
|
Laboratory of Genetics and Molecular Cardiology, University of São Paulo
Study: HipercolBrasil
Accession: SCV000588605.1 First in ClinVar: Aug 13, 2017 Last updated: Aug 13, 2017 |
Observation:
2
Observation 1
Collection method: research
Allele origin: germline
Affected status: unknown
Comment on evidence:
%MAF(ExAC):0.004942
Observation 2
Collection method: research
Allele origin: germline
Affected status: unknown
Comment on evidence:
Assay description:Comp Htz (with p.(Cys89Arg) or with p.(Pro685Leu)) patients' fibroblasts, 125I-LDL assays / Heterologous cells (CHO), FACS assays / Htz patients' Epstein-Barr virus transformed lymphocytes, … (more)
Assay description:Comp Htz (with p.(Cys89Arg) or with p.(Pro685Leu)) patients' fibroblasts, 125I-LDL assays / Heterologous cells (CHO), FACS assays / Htz patients' Epstein-Barr virus transformed lymphocytes, FACS assays (less)
Result:
2-5% LDLR activity / 50% LDLR activity / 35-75% LDLR activity
|
|
|
Pathogenic
(Feb 27, 2018)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Hypercholesterolemia, familial, 1 |
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Study: AGHI-GT-HudsonAlpha
Accession: SCV000778604.1 First in ClinVar: May 26, 2018 Last updated: May 26, 2018 |
Observation 1
Collection method: research
Allele origin: unknown
Affected status: yes
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Oct 31, 2018)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Hypercholesterolemia, familial, 1 |
Fulgent Genetics, Fulgent Genetics
Accession: SCV000894177.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
|
|
Pathogenic
(Oct 29, 2018)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Hypercholesterolemia, familial, 1 |
Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen
Accession: SCV000987017.1
First in ClinVar: Aug 31, 2019 Last updated: Aug 31, 2019 |
Comment:
show
This nucleotide substitution causes an exchange of the amino acid of glycine (Gly) to glutamic acid (Glu) p.Gly592Glu (legacy name: p.Gly571Glu). This change has already been described in the literature as FH Sicily, FH Foggia 1 and FH Naples 4 and has been found in patients with familial hypercholesterolemia and is associated with elevated cholesterol and LDL-C levels. It results in a reduced amount of biologically active LDL receptors on the cell surface. We observed this variant in a patient with TC up to 350 mg/dl and LDL-C approx 290 mg/dl at the age of 48 and in a patient with TC up to 300 mg/dl and LDL-C approx 250 mg/dl at the age of 5. PMID: 1301956, 27998977, 22390909, 26036859. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Mar 03, 2019)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Hypercholesterolemia, familial, 1 |
Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia
Accession: SCV001432593.1
First in ClinVar: Sep 19, 2020 Last updated: Sep 19, 2020 |
Observation:
8
Observation 1
Collection method: research
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
Clinical Features:
Dutch Lipid Clinic Network Criteria score (present) , low-density lipoprotein cholesterol level (present)
Comment on clinical features:
8 (clinical Dutch Lipid Clinic Network Criteria score); 6.71 mmol/L (calculated low-density lipoprotein cholesterol level)
Platform type: next-gen sequencing
Platform name: MiSeq
Observation 2
Collection method: research
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
Clinical Features:
Dutch Lipid Clinic Network Criteria score (present) , low-density lipoprotein cholesterol level (present)
Comment on clinical features:
9 (clinical Dutch Lipid Clinic Network Criteria score); 6.57 mmol/L (calculated low-density lipoprotein cholesterol level)
Platform type: next-gen sequencing
Platform name: MiSeq
Observation 3
Collection method: research
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
Clinical Features:
Dutch Lipid Clinic Network Criteria score (present) , low-density lipoprotein cholesterol level (present)
Comment on clinical features:
7 (clinical Dutch Lipid Clinic Network Criteria score); 10.3 mmol/L (calculated low-density lipoprotein cholesterol level)
Platform type: next-gen sequencing
Platform name: MiSeq
Observation 4
Collection method: research
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
Clinical Features:
Dutch Lipid Clinic Network Criteria score (present) , low-density lipoprotein cholesterol level (present)
Comment on clinical features:
8 (clinical Dutch Lipid Clinic Network Criteria score); 6.3 mmol/L (calculated low-density lipoprotein cholesterol level)
Platform type: next-gen sequencing
Platform name: MiSeq
Observation 5
Collection method: research
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
Clinical Features:
Dutch Lipid Clinic Network Criteria score (present) , low-density lipoprotein cholesterol level (present)
Comment on clinical features:
8 (clinical Dutch Lipid Clinic Network Criteria score); 9.1 mmol/L (calculated low-density lipoprotein cholesterol level)
Platform type: next-gen sequencing
Platform name: MiSeq
Observation 6
Collection method: research
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
Clinical Features:
Dutch Lipid Clinic Network Criteria score (present) , low-density lipoprotein cholesterol level (present)
Comment on clinical features:
6 (clinical Dutch Lipid Clinic Network Criteria score); 5.82 mmol/L (calculated low-density lipoprotein cholesterol level)
Platform type: next-gen sequencing
Platform name: MiSeq
Observation 7
Collection method: research
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
Clinical Features:
Dutch Lipid Clinic Network Criteria score (present) , low-density lipoprotein cholesterol level (present)
Comment on clinical features:
8 (clinical Dutch Lipid Clinic Network Criteria score); 6.01 mmol/L (calculated low-density lipoprotein cholesterol level)
Platform type: next-gen sequencing
Platform name: MiSeq
Observation 8
Collection method: research
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
Clinical Features:
Dutch Lipid Clinic Network Criteria score (present) , low-density lipoprotein cholesterol level (present)
Comment on clinical features:
12 (clinical Dutch Lipid Clinic Network Criteria score); 6.93 mmol/L (calculated low-density lipoprotein cholesterol level)
Platform Type: next-gen sequencing
Platform Name: MiSeq
|
|
|
Likely pathogenic
(May 24, 2021)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Hypercholesterolemia, familial, 1 |
Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II
Accession: SCV001653652.1
First in ClinVar: Jun 08, 2021 Last updated: Jun 08, 2021 |
Comment:
show
Reduced activity, in stimulated T-lymphocytes and EBV-transformed B-lymphocytes. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 49
Ethnicity/Population group: Caucasian
Geographic origin: Italy
|
|
|
Pathogenic
(Feb 23, 2022)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002503265.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 3
Secondary finding: no
Platform type: NGS
|
|
|
Pathogenic
(May 01, 2021)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Hypercholesterolemia, familial, 1 |
Laan Lab, Human Genetics Research Group, University of Tartu
Accession: SCV002538607.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
Observation 1
Collection method: research
Allele origin: unknown
Affected status: unknown
Number of individuals with the variant: 1
Clinical Features:
Non-obstructive azoospermia (present)
Zygosity: 1 Single Heterozygote
Secondary finding: yes
Method: exome sequencing
|
|
|
Pathogenic
(Jun 02, 2022)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004227680.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Jun 24, 2022)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Hypercholesterolemia, familial, 1 |
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Accession: SCV005398525.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Comment:
show
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with hypercholesterolemia, familial, 1 (MIM#143890). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). Biallelic individuals have an earlier onset and more severe disease (PMID 24404629). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to glutamic acid. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (16 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (4 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated low-density lipoprotein-receptor YWTD domain (NCBI domain). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals (ClinVar, ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, PMID: 34906454). (SP) 0901 - This variant has strong evidence for segregation with disease (ClinVar, ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, PMID: 34906454). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies have demonstrated reduced residual LDLR activity compared with controls in EBV-transformed B-lymphocytes and T-lymphocytes from FH patients with this variant (PMID: 21865347). (SP) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Dec 03, 2024)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Cardiovascular phenotype |
Ambry Genetics
Accession: SCV002714823.3
First in ClinVar: Nov 29, 2022 Last updated: Jan 13, 2025 |
Comment:
show
The c.1775G>A (p.G592E) alteration is located in coding exon 12 of the LDLR gene. This alteration results from a G to A substitution at nucleotide position 1775, causing the glycine (G) at amino acid position 592 to be replaced by a glutamic acid (E). Based on data from gnomAD, the A allele has an overall frequency of 0.006% (16/282866) total alleles studied. The highest observed frequency was 0.012% (15/129176) of European (non-Finnish) alleles. This variant, also known as FH-Sicily and G571E, has been detected in many unrelated individuals with familial hypercholesterolemia (FH) (Hobbs, 1992; Miltiadous, 2001; Romano, 2011; Susan-Resiga, 2017). In addition, this variant has been reported as one of the most common amongst Czech, Polish, German, Austrian, and Slovak FH cohorts (Chmara, 2010; Tichý, 2012; Gabová, 2017). This amino acid position is highly conserved in available vertebrate species. The p.G592E amino acid is located in the EGF precursor-like domain. This variant has been reported to impact protein function (Hobbs, 1992; Romano, 2011; Susan-Resiga, 2017). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Likely pathogenic
(Nov 05, 2016)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Hypercholesterolemia, familial, 1
(Autosomal dominant inheritance)
|
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation
Additional submitter:
Centre of Molecular Biology and Gene Therapy, University Hospital Brno
Accession: SCV000540837.2
First in ClinVar: Apr 08, 2017 Last updated: Apr 13, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: inherited
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: inherited
Affected status: yes
Number of individuals with the variant: 277
Clinical Features:
Hypercholesterolemia (present) , Xanthelasma (present) , Tendon xanthoma (present) , Corneal arcus (present) , Ischemic stroke (present)
Zygosity: 2 Homozygotes, 272 Single Heterozygotes, 3 Compound Heterozygotes
Family history: yes
Age: 8-61 years
Sex: mixed
Ethnicity/Population group: Caucasian
Geographic origin: Czech Republic
Tissue: Whole blood
Platform type: Sanger sequencing
|
|
|
Pathogenic
(Mar 30, 2017)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Familial Hypercholesterolemia |
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille
Accession: SCV000583883.2
First in ClinVar: Apr 16, 2017 Last updated: Apr 13, 2025
Comment:
ACMG Guidelines: Pathogenic (ii)
|
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 5
Clinical Features:
Hyperbetalipoproteinemia (present) , Hypercholesterolemia (present)
Comment on clinical features:
"Dutch Lipid Clinic" Diagnostic Scoring ESC/EAS Guidelines 2016 - PMID: 27567407
Indication for testing: Familial Hypercholesterolemia
Test name: Genetic Testing for FH
Sex: mixed
Geographic origin: France
Comment on evidence:
Dutch Lipid Clinic Scoring : Definite FH
Secondary finding: no
|
|
|
Pathogenic
(Jul 22, 2024)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Hypercholesterolemia, familial, 1
(Autosomal dominant inheritance)
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001429254.5
First in ClinVar: Aug 17, 2020 Last updated: Apr 13, 2025 |
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: yes
Clinical Features:
Elevated circulating LDL-C concentration (present)
Sex: male
|
|
|
Likely pathogenic
(-)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Familial hypercholesterolemia |
Laboratory of Molecular Genetics, National Medical Research Center for Therapy and Preventive Medicine
Accession: SCV001482461.2
First in ClinVar: Mar 07, 2021 Last updated: Apr 13, 2025 |
Observation:
4
Observation 1
Collection method: research
Allele origin: germline
Affected status: yes
Zygosity: 1 Single Heterozygote
Age: 50-59 years
Sex: male
Observation 2
Collection method: research
Allele origin: germline
Affected status: yes
Zygosity: 1 Single Heterozygote
Age: 50-59 years
Sex: male
Observation 3
Collection method: research
Allele origin: germline
Affected status: yes
Zygosity: 1 Single Heterozygote
Age: 60-69 years
Sex: male
Observation 4
Collection method: research
Allele origin: germline
Affected status: yes
Zygosity: 1 Single Heterozygote
Age: 50-59 years
Sex: male
|
|
|
Pathogenic
(Dec 15, 2021)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
see cases
|
Centre of Medical Genetics, University Hospital Muenster
Accession: SCV002506438.3
First in ClinVar: May 07, 2022 Last updated: Apr 13, 2025 |
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: yes
Number of individuals with the variant: 1
Clinical Features:
Hypercholesterolemia (present)
Zygosity: 1 Single Heterozygote
Age: 0-9 years
Sex: female
Tissue: blood
Platform type: next-gen sequencing
Platform name: NovaSeq 6000
|
|
|
Pathogenic
(Jan 02, 2024)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Familial hypercholesterolemia |
Color Diagnostics, LLC DBA Color Health
Accession: SCV000903573.5
First in ClinVar: May 20, 2019 Last updated: May 03, 2025 |
Comment:
show
This missense variant replaces glycine with glutamic acid at codon 592 in the fifth LDLR type B repeat of the LDLR protein. This variant is also known as p.Gly571Glu in the mature protein and as FH-Sicily, FH Foggia-1, FH Naples. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant results in a partial loss of LDLR activity (PMID: 21865347). The variant has been identified in over 200 heterozygous and homozygous familial hypercholesterolemia patients from multiple European ethnicities (PMID: 1301956, 9654205, 11139254, 11139254, 11317361, 11641914, 11754108, 15199436, 15241806, 17765246, 18263977, 20145306, 20663204, 21310417, 21925044, 22698793, 23375686, 25461735, 25463123, 25487149, 26020417, 31947532, 35741760). This variant is highly recurrent in Slovakia, Czech Republic, and Poland (PMID: 26238499). A different variant occurring at the same codon, p.Gly592Arg, is a likely pathogenic mutation (Clinvar variation ID: 373769), indicating that glycine at this position is important for LDLR protein function. This variant has been identified in 16/282866 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Platform type: NGS
|
|
|
Pathogenic
(-)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Hypercholesterolemia, familial, 1
(Autosomal dominant inheritance)
|
UCSF Pediatric Lipid Clinic, University of California, San Francisco
Accession: SCV000998546.3
First in ClinVar: Nov 07, 2019 Last updated: Aug 03, 2025 |
Comment:
show
The p.G592E variant in LDLR segregates with elevated level of LDL-C in a family of over ten individuals. The allele frequency of this variant in the population is 0.00004 based on the GnomAD database. (less)
Observation: 1
Collection method: clinical testing
Allele origin: inherited
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: inherited
Affected status: yes
Number of individuals with the variant: 4
Clinical Features:
Hypercholesterolemia (present)
Test name: Whole exome sequencing
Zygosity: 0 Homozygote, 3 Single Heterozygotes, 1 Compound Heterozygote, 0 Hemizygote
Age: 6-70 years
Sex: mixed
Ethnicity/Population group: European
Comment on evidence:
"variation affecting protein function" was previously submitted as the functional consequence, but without providing the result of a functional assay.
Platform type: Next-generation exome sequencing
Platform name: HiSeq2500
|
|
|
Pathogenic
(Jan 23, 2025)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Hypercholesterolemia, familial, 1 |
Revvity Omics, Revvity
Accession: SCV003827125.3
First in ClinVar: Mar 04, 2023 Last updated: Sep 06, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Jan 31, 2026)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Familial hypercholesterolemia |
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000544669.12
First in ClinVar: Apr 16, 2017 Last updated: Mar 07, 2026 |
Comment:
show
This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 592 of the LDLR protein (p.Gly592Glu). This variant is present in population databases (rs137929307, gnomAD 0.01%). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 15864114, 20663204, 21310417). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of European ancestry (PMID: 21925044, 23375686, 26238499). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this LDLR variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 377,766 individuals referred to our laboratory for LDLR testing. This variant is also known as p.Gly571Glu. ClinVar contains an entry for this variant (Variation ID: 161271). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Aug 29, 2025)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Familial hypercholesterolemia |
Natera, Inc.
Accession: SCV001461319.2
First in ClinVar: Jan 02, 2021 Last updated: Apr 04, 2026 |
Comment:
show
The c.1775G>A variant in LDLR is a missense variant predicted to cause substitution of glycine to glutamic acid at amino acid 592. This variant has been observed in one or more individuals affected with the associated recessive disease, as either homozygous or compound heterozygous with a second variant (PMID: 31947532). Additionally, this variant has been observed to segregate in affected family members (PMID: 31947532). Functional studies show that this variant may disrupt protein function (PMID: 27998977). A different variant at the same position has been determined to be Pathogenic or Likely Pathogenic. Computational prediction algorithms indicate this variant is likely to affect gene or protein function. Given the available evidence, this variant is classified as Pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Apr 27, 2026)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Dasa
Accession: SCV007599662.1
First in ClinVar: May 30, 2026 Last updated: May 30, 2026 |
Comment:
show
NM_000527.5(LDLR):c.1775G>A (p.Gly592Glu) is a missense variant that results in the substitution of glycine with glutamic acid. Segregation evidence has been reported in affected families. Functional evidence supports a deleterious effect on the gene or gene product (PMID: 21865347). This variant has been reported in individuals with related phenotype (PMID: 21865347). Multiple computational predictions support a deleterious effect on the gene or gene product. The variant is present at low frequency in population datasets. Based on the available data, this variant is classified as pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Feb 01, 2025)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
CeGaT Center for Human Genetics Tuebingen
Accession: SCV003918065.25
First in ClinVar: Apr 23, 2023 Last updated: Jun 20, 2026 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 5
|
|
|
Likely pathogenic
(Mar 01, 2016)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Familial hypercholesterolemia
(Autosomal dominant inheritance)
|
Fundacion Hipercolesterolemia Familiar
Study: SAFEHEART
Accession: SCV000607638.1 First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
Observation:
2
Observation 1
Collection method: research
Allele origin: germline
Affected status: unknown
Comment on evidence:
%MAF(ExAC):0.004942
Observation 2
Collection method: research
Allele origin: germline
Affected status: unknown
Comment on evidence:
Comp Htz (with p.(Cys89Arg) or with p.(Pro685Leu)) patients' fibroblasts, 125I-LDL assays / Heterologous cells (CHO), FACS assays / Htz patients' Epstein-Barr virus transformed lymphocytes, FACS … (more)
Comp Htz (with p.(Cys89Arg) or with p.(Pro685Leu)) patients' fibroblasts, 125I-LDL assays / Heterologous cells (CHO), FACS assays / Htz patients' Epstein-Barr virus transformed lymphocytes, FACS assays (less)
Result:
2-5% LDLR activity / 50% LDLR activity / 35-75% LDLR activity
|
|
|
Likely pathogenic
(Mar 01, 2016)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Familial hypercholesterolemia
(Autosomal dominant inheritance)
|
Iberoamerican FH Network
Accession: SCV000748115.1
First in ClinVar: May 19, 2018 Last updated: May 19, 2018
Comment:
Variant present in the databases from Chile and Uruguay
|
Observation:
2
Observation 1
Collection method: research
Allele origin: germline
Affected status: unknown
Comment on evidence:
%MAF(ExAC):0.004942
Observation 2
Collection method: research
Allele origin: germline
Affected status: unknown
Comment on evidence:
Assay Description:Comp Htz (with p.(Cys89Arg) or with p.(Pro685Leu)) patients' fibroblasts, 125I-LDL assays / Heterologous cells (CHO), FACS assays / Htz patients' Epstein-Barr virus transformed lymphocytes, … (more)
Assay Description:Comp Htz (with p.(Cys89Arg) or with p.(Pro685Leu)) patients' fibroblasts, 125I-LDL assays / Heterologous cells (CHO), FACS assays / Htz patients' Epstein-Barr virus transformed lymphocytes, FACS assays (less)
Result:
2-5% LDLR activity / 50% LDLR activity / 35-75% LDLR activity
|
|
|
Pathogenic
(Sep 03, 2024)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Hypercholesterolemia, familial, 1
(Semidominant inheritance)
|
All of Us Research Program, National Institutes of Health
Accession: SCV004822500.2
First in ClinVar: Apr 20, 2024 Last updated: Dec 14, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
|
Comment:
show
This missense variant (also known as p.Gly571Glu in the mature protein and as FH-Sicily, FH Foggia-1, FH Naples) is located in the fifth LDLR type B repeat of the LDLR protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant results in a partial loss of LDLR activity (PMID: 21865347). The variant has been identified in over 200 heterozygous and homozygous familial hypercholesterolemia patients from multiple European ethnicities (PMID: 1301956, 9654205, 11139254, 11139254, 11317361, 11641914, 11754108, 15199436, 15241806, 17765246, 18263977, 20145306, 20663204, 21310417, 21925044, 22698793, 23375686, 25461735, 25463123, 25487149, 26020417, 31947532, 35741760). This variant is highly recurrent in Slovakia, Czech Republic, and Poland (PMID: 26238499). A different variant occurring at the same codon, p.Gly592Arg, is a likely pathogenic mutation (Clinvar variation ID: 373769), indicating that glycine at this position is important for LDLR protein function. This variant has been identified in 16/282866 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Number of individuals with the variant: 16
Zygosity: 16 Single Heterozygotes
|
|
|
Pathogenic
(Sep 25, 2025)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Familial hypercholesterolaemia |
Genetics Laboratory, Great Ormond Street Hospital NHS Foundation Trust, North Thames Genomic Laboratory Hub
Accession: SCV007106039.1
First in ClinVar: Dec 01, 2025 Last updated: Dec 01, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
not provided |
Clinical Genetics, Academic Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001918371.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Jun 01, 2014)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Hypercholesterolaemia
(Autosomal dominant inheritance)
|
CSER _CC_NCGL, University of Washington
Study: ESP 6500 variant annotation
Accession: SCV000190290.1 First in ClinVar: Dec 07, 2014 Last updated: Dec 07, 2014
Comment:
Variants classified for the Actionable exomic incidental findings in 6503 participants: challenges of variant classification manuscript
|
Observation: 1
Collection method: research
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: research
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
not provided |
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Study: VKGL Data-share Consensus
Accession: SCV001951679.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Dec 18, 2023)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Hypercholesterolemia, familial, 1 |
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein
Accession: SCV006323997.1
First in ClinVar: Sep 06, 2025 Last updated: Sep 06, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Secondary finding: yes
|
|
|
Pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Familial hypercholesterolemia |
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum
Accession: SCV000606511.1
First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
Observation: 1
Collection method: research
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: research
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
not provided |
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV000733827.4 First in ClinVar: Apr 09, 2018 Last updated: Sep 08, 2021 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
not provided
(-)
N
Not contributing to aggregate classification
|
no classification provided
(in vitro)
|
not provided |
Dept. of Genetics and Pharmacogenomics, Merck Research Labs
Accession: SCV000189576.2
First in ClinVar: Feb 28, 2015 Last updated: Aug 03, 2025
Comment:
In vitro functional profiling of LDL-receptor missense alleles identified through large-scale association testing
|
Observation: 1
Collection method: in vitro
Allele origin: not applicable
Affected status: not applicable
Observation 1
Collection method: in vitro
Allele origin: not applicable
Affected status: not applicable
Cell line: HeLa Kyoto
Comment on evidence:
"no known functional consequence" was previously submitted as the functional consequence for NM_000527.4:c.1775g>a, but without providing the result of a functional assay. The following comment … (more)
"no known functional consequence" was previously submitted as the functional consequence for NM_000527.4:c.1775g>a, but without providing the result of a functional assay. The following comment was also provided: non-disruptive missense (less)
|
|
Comment:
Comment:
Variant summary: The LDLR c.1775G>A (p.Gly592Glu) variant involves the alteration of a conserved nucleotide. Gly592 is highly conserved across species, and 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 6/121608 control chromosomes at a frequency of 0.0000493, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0025031). This variant has been reported in many FH patients in both heterozygous, compound heterozygous, and homozygous states with evidence of co-segregation in some of the families. Functional studies indicate that the variant of interest has defective LDL receptor activity. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic/likely pathogenic. Taken together, this variant is classified as pathogenic.
Comment:
The p.Gly592Glu variant in LDLR has been reported in >200 Caucasian individuals with familial hypercholesterolemia (FH) and segregated with disease in >30 affected relatives from >3 families (Gorski 1998 PMID: 9654205, Miltiadous 2001 PMID: 11317361, Kuhrova 2002 PMID: 11754108, Kublaska 2008 PMID: 18263977, Bourbon 2008 PMID: 17765246, Chmara 2010 PMID: 20145306, Diakou 2011 PMID: 21925044, Tichy 2012 PMID: 22698793, Bertolini 2013 PMID: 23375686, Do 2015 PMID: 25487149, Medeiros 2015 PMID: 26020417, Jannes 2015 PMID: 25461735, Braenne 2015 PMID: 26036859). This variant has also been identified in 0.01% (15/129176) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with the frequency of FH in the general population. Furthermore, in vitro functional studies support that the p.Gly592Glu variant may impact protein function (Romano 2011 PMID: 21865347). In summary, this variant meets criteria to be classified as pathogenic for familial hypercholesterolemia in an autosomal dominant manner based upon presence in multiple affected individuals and segregation studies. ACMG/AMP Criteria applied: PS4, PP1_Strong, PS3_Supporting.
Comment:
Published functional studies demonstrate that G592E results in reduced LDL receptor activity (Hobbs et al., 1992); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as p.G571E, FH Sicily, FH Foggi, FH Naples-4; This variant is associated with the following publications: (PMID: 27998977, 11524740, 24627126, 25282520, 34167030, 32423031, 35339733, 34697415, 21310417, 15864114, 26238499, 11641914, 22390909, 25637381, 21865347, 20145306, 26036859, 20663204, 15523646, 11848618, 26666465, 27824480, 21382890, 27050191, 19062533, 27578104, 25463123, 27784735, 22294733, 22698793, 26020417, 26892515, 15890894, 23833242, 18263977, 25487149, 16627557, 25936317, 23375686, 24507775, 26723464, 28965616, 15241806, 19026292, 17539906, 9654205, 17196209, 11139254, 20506408, 11754108, 11317361, 31617323, 31447099, 21925044, 33975813, 33303402, 32719484, 32660911, 33269076, 32770674, 32977124, 31589614, 32041611, 33740630, 33418990, 34037665, 34456049, 32009526, 35741760, 35913489, 33955087, 30710474, 1301956)
Comment:
Internal analysis revealed that the variant was statistically enriched in familial hypercholesterolemia cases over matched controls in the published literature (PMID: 17765246 (2008), 20145306 (2010), 21925044 (2011), 22698793 (2012), and 23375686 (2013)). Additionally, reduced LDL receptor activity was observed from fibroblasts and peripheral blood T-lymphocytes extracted from patients with this variant ((PMID: 1301956 (1992) and 21865347 (2011)).
Comment:
The LDLR c.1775G>A; p.Gly592Glu variant (rs137929307), also published as Gly571Glu, FH Sicily, FH Foggia 1, and FH Naples 4, is reported in the literature in numerous heterozygous, homozygous, and compound heterozygous individuals affected with hypercholesterolemia and has been reported to segregate with disease in families (Bertolini 2020, Bertolini 2013, Braenne 2016, Hobbs 1992, Meshkov 2021, Wong 2019). This variant is found in the non-Finnish European population with an allele frequency of 0.01% (15/129,176 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses predict that this variant is deleterious (REVEL: 0.938), and functional analyses indicate reduced residual activity of the variant protein (Romano 2011). Based on available information, this variant is considered to be pathogenic. References: Bertolini S et al. Homozygous familial hypercholesterolemia in Italy: Clinical and molecular features. Atherosclerosis. 2020 Nov;312:72-78. PMID: 32977124. Bertolini S et al. Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy. Atherosclerosis. 2013 Apr;227(2):342-8. PMID: 23375686. Braenne I et al. Systematic analysis of variants related to familial hypercholesterolemia in families with premature myocardial infarction. Eur J Hum Genet. 2016 Feb;24(2):191-7. PMID: 26036859. Hobbs et al. Molecular genetics of the LDL receptor gene in familial hypercholesterolemia. Hum Mutat. 1992;1(6):445-66. PMID: 1301956. Meshkov A et al. The LDLR, APOB, and PCSK9 Variants of Index Patients with Familial Hypercholesterolemia in Russia. Genes (Basel). 2021 Jan 6;12(1):66. PMID: 33418990. Romano M et al. An improved method on stimulated T-lymphocytes to functionally characterize novel and known LDLR mutations. J Lipid Res. 2011 Nov;52(11):2095-100. PMID: 21865347. Wong KHY et al. Three patients with homozygous familial hypercholesterolemia: Genomic sequencing and kindred analysis. Mol Genet Genomic Med. 2019 Dec;7(12):e1007. PMID: 31617323.
Comment:
This is a nonsynonymous variant in the LDLR gene (OMIM: 606945). Pathogenic variants in this gene have been associated with autosomal semidominant familial hypercholesterolemia 1. This variant has been reported in many unrelated affected individuals (PS4), and it has been observed to segregate with disease in many families in these reports (PP1) (reports include PMID: 20145306, 20663204, 21310417, 21925044, 22698793, 23375686, 25461735, 25463123, 25487149, 26020417, 26238499). The clinical symptoms reported for these individuals are highly specific for autosomal semidominant familial hypercholesterolemia 1, which has a limited genetic etiology (PP4). This variant Functional studies have shown that this variant alters LDLR protein function (PMID: 21865347) (PS3_Moderate), and multiple computational algorithms predict a deleterious effect for this variant (REVEL score: 0.938) (PP3). This variant has a 0.0060% maximum allele frequency in non-founder control populations (https://gnomad.broadinstitute.org/) (PM2). Other reputable laboratories have reported this variant as pathogenic or likely pathogenic, and this classification has been validated by an expert panel in ClinVar (PP5). Based on the current evidence, this variant is classified as pathogenic for autosomal semidominant familial hypercholesterolemia 1.
Comment:
0/220 non-FH alleles; 0/77 healthy control individuals
Comment:
subjects mutated among 2600 FH index cases screened = 11 , family members = 3 with co-segregation / previously described in association with FH, 5 to 15% LDLR Activity/software prediction damaging
Comment:
This nucleotide substitution causes an exchange of the amino acid of glycine (Gly) to glutamic acid (Glu) p.Gly592Glu (legacy name: p.Gly571Glu). This change has already been described in the literature as FH Sicily, FH Foggia 1 and FH Naples 4 and has been found in patients with familial hypercholesterolemia and is associated with elevated cholesterol and LDL-C levels. It results in a reduced amount of biologically active LDL receptors on the cell surface. We observed this variant in a patient with TC up to 350 mg/dl and LDL-C approx 290 mg/dl at the age of 48 and in a patient with TC up to 300 mg/dl and LDL-C approx 250 mg/dl at the age of 5. PMID: 1301956, 27998977, 22390909, 26036859.
Comment:
Reduced activity, in stimulated T-lymphocytes and EBV-transformed B-lymphocytes.
Comment:
PP1_strong, PP3, PP4, PM2, PS3, PS4
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with hypercholesterolemia, familial, 1 (MIM#143890). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). Biallelic individuals have an earlier onset and more severe disease (PMID 24404629). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to glutamic acid. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (16 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (4 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated low-density lipoprotein-receptor YWTD domain (NCBI domain). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals (ClinVar, ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, PMID: 34906454). (SP) 0901 - This variant has strong evidence for segregation with disease (ClinVar, ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, PMID: 34906454). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies have demonstrated reduced residual LDLR activity compared with controls in EBV-transformed B-lymphocytes and T-lymphocytes from FH patients with this variant (PMID: 21865347). (SP) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
The c.1775G>A (p.G592E) alteration is located in coding exon 12 of the LDLR gene. This alteration results from a G to A substitution at nucleotide position 1775, causing the glycine (G) at amino acid position 592 to be replaced by a glutamic acid (E). Based on data from gnomAD, the A allele has an overall frequency of 0.006% (16/282866) total alleles studied. The highest observed frequency was 0.012% (15/129176) of European (non-Finnish) alleles. This variant, also known as FH-Sicily and G571E, has been detected in many unrelated individuals with familial hypercholesterolemia (FH) (Hobbs, 1992; Miltiadous, 2001; Romano, 2011; Susan-Resiga, 2017). In addition, this variant has been reported as one of the most common amongst Czech, Polish, German, Austrian, and Slovak FH cohorts (Chmara, 2010; Tichý, 2012; Gabová, 2017). This amino acid position is highly conserved in available vertebrate species. The p.G592E amino acid is located in the EGF precursor-like domain. This variant has been reported to impact protein function (Hobbs, 1992; Romano, 2011; Susan-Resiga, 2017). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Comment:
Criteria applied: PS4,PP1_STR,PS3_MOD,PM2,PP3
Comment:
ACMG categories: PS3,PM1,PP1,PP3,PP4,PP5
Comment:
This missense variant replaces glycine with glutamic acid at codon 592 in the fifth LDLR type B repeat of the LDLR protein. This variant is also known as p.Gly571Glu in the mature protein and as FH-Sicily, FH Foggia-1, FH Naples. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant results in a partial loss of LDLR activity (PMID: 21865347). The variant has been identified in over 200 heterozygous and homozygous familial hypercholesterolemia patients from multiple European ethnicities (PMID: 1301956, 9654205, 11139254, 11139254, 11317361, 11641914, 11754108, 15199436, 15241806, 17765246, 18263977, 20145306, 20663204, 21310417, 21925044, 22698793, 23375686, 25461735, 25463123, 25487149, 26020417, 31947532, 35741760). This variant is highly recurrent in Slovakia, Czech Republic, and Poland (PMID: 26238499). A different variant occurring at the same codon, p.Gly592Arg, is a likely pathogenic mutation (Clinvar variation ID: 373769), indicating that glycine at this position is important for LDLR protein function. This variant has been identified in 16/282866 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
The p.G592E variant in LDLR segregates with elevated level of LDL-C in a family of over ten individuals. The allele frequency of this variant in the population is 0.00004 based on the GnomAD database.
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 592 of the LDLR protein (p.Gly592Glu). This variant is present in population databases (rs137929307, gnomAD 0.01%). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 15864114, 20663204, 21310417). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of European ancestry (PMID: 21925044, 23375686, 26238499). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this LDLR variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 377,766 individuals referred to our laboratory for LDLR testing. This variant is also known as p.Gly571Glu. ClinVar contains an entry for this variant (Variation ID: 161271). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Comment:
The c.1775G>A variant in LDLR is a missense variant predicted to cause substitution of glycine to glutamic acid at amino acid 592. This variant has been observed in one or more individuals affected with the associated recessive disease, as either homozygous or compound heterozygous with a second variant (PMID: 31947532). Additionally, this variant has been observed to segregate in affected family members (PMID: 31947532). Functional studies show that this variant may disrupt protein function (PMID: 27998977). A different variant at the same position has been determined to be Pathogenic or Likely Pathogenic. Computational prediction algorithms indicate this variant is likely to affect gene or protein function. Given the available evidence, this variant is classified as Pathogenic.
Comment:
NM_000527.5(LDLR):c.1775G>A (p.Gly592Glu) is a missense variant that results in the substitution of glycine with glutamic acid. Segregation evidence has been reported in affected families. Functional evidence supports a deleterious effect on the gene or gene product (PMID: 21865347). This variant has been reported in individuals with related phenotype (PMID: 21865347). Multiple computational predictions support a deleterious effect on the gene or gene product. The variant is present at low frequency in population datasets. Based on the available data, this variant is classified as pathogenic.
Comment:
LDLR: PP1:Strong, PM2, PM5, PS4:Moderate, PS3:Supporting
Comment:
This missense variant (also known as p.Gly571Glu in the mature protein and as FH-Sicily, FH Foggia-1, FH Naples) is located in the fifth LDLR type B repeat of the LDLR protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant results in a partial loss of LDLR activity (PMID: 21865347). The variant has been identified in over 200 heterozygous and homozygous familial hypercholesterolemia patients from multiple European ethnicities (PMID: 1301956, 9654205, 11139254, 11139254, 11317361, 11641914, 11754108, 15199436, 15241806, 17765246, 18263977, 20145306, 20663204, 21310417, 21925044, 22698793, 23375686, 25461735, 25463123, 25487149, 26020417, 31947532, 35741760). This variant is highly recurrent in Slovakia, Czech Republic, and Poland (PMID: 26238499). A different variant occurring at the same codon, p.Gly592Arg, is a likely pathogenic mutation (Clinvar variation ID: 373769), indicating that glycine at this position is important for LDLR protein function. This variant has been identified in 16/282866 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
PS4_strong, PM2_moderate, PP3_supporting, PS3_moderate, PP1_strong
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Familial Hypercholesterolemia. | Adam MP | - | 2025 | PMID: 24404629 |
| Identification of New Genetic Determinants in Pediatric Patients with Familial Hypercholesterolemia Using a Custom NGS Panel. | Rutkowska L | Genes | 2022 | PMID: 35741760 |
| Actionable secondary findings following exome sequencing of 836 non-obstructive azoospermia cases and their value in patient management. | Kasak L | Human reproduction (Oxford, England) | 2022 | PMID: 35535697 |
| The Clinical Genome Resource (ClinGen) Familial Hypercholesterolemia Variant Curation Expert Panel consensus guidelines for LDLR variant classification. | Chora JR | Genetics in medicine : official journal of the American College of Medical Genetics | 2022 | PMID: 34906454 |
| LDLR variants functional characterization: Contribution to variant classification. | Alves AC | Atherosclerosis | 2021 | PMID: 34167030 |
| Limited-Variant Screening vs Comprehensive Genetic Testing for Familial Hypercholesterolemia Diagnosis. | Sturm AC | JAMA cardiology | 2021 | PMID: 34037665 |
| A case of homozygous familial hypercholesterolemia with an atypical phenotype and delayed clinical symptoms. | Kyselak O | Journal of clinical lipidology | 2021 | PMID: 33975813 |
| Molecular genetic testing for autosomal dominant hypercholesterolemia in 29,449 Norwegian index patients and 14,230 relatives during the years 1993-2020. | Leren TP | Atherosclerosis | 2021 | PMID: 33740630 |
| The LDLR, APOB, and PCSK9 Variants of Index Patients with Familial Hypercholesterolemia in Russia. | Meshkov A | Genes | 2021 | PMID: 33418990 |
| Combined hyperlipidemia is genetically similar to isolated hypertriglyceridemia. | Gill PK | Journal of clinical lipidology | 2021 | PMID: 33303402 |
| Identification of novel variants in the LDLR gene in Russian patients with familial hypercholesterolemia using targeted sequencing. | Miroshnikova VV | Biomedical reports | 2021 | PMID: 33269076 |
| Diagnostic yield of sequencing familial hypercholesterolemia genes in individuals with primary hypercholesterolemia. | Lamiquiz-Moneo I | Revista espanola de cardiologia (English ed.) | 2021 | PMID: 32660911 |
| Homozygous familial hypercholesterolemia in Italy: Clinical and molecular features. | Bertolini S | Atherosclerosis | 2020 | PMID: 32977124 |
| Mutation spectrum and polygenic score in German patients with familial hypercholesterolemia. | Rieck L | Clinical genetics | 2020 | PMID: 32770674 |
| Population genetic screening efficiently identifies carriers of autosomal dominant diseases. | Grzymski JJ | Nature medicine | 2020 | PMID: 32719484 |
| Six years' experience with LipidSeq: clinical and research learnings from a hybrid, targeted sequencing panel for dyslipidemias. | Dron JS | BMC medical genomics | 2020 | PMID: 32041611 |
| A Real-World Experience of Clinical, Biochemical and Genetic Assessment of Patients with Homozygous Familial Hypercholesterolemia. | Di Taranto MD | Journal of clinical medicine | 2020 | PMID: 31947532 |
| Three patients with homozygous familial hypercholesterolemia: Genomic sequencing and kindred analysis. | Wong KHY | Molecular genetics & genomic medicine | 2019 | PMID: 31617323 |
| Harmonizing Clinical Sequencing and Interpretation for the eMERGE III Network. | eMERGE Consortium. Electronic address: agibbs@bcm.edu | American journal of human genetics | 2019 | PMID: 31447099 |
| Lipid profile and genetic status in a familial hypercholesterolemia pediatric population: exploring the LDL/HDL ratio. | Di Taranto MD | Clinical chemistry and laboratory medicine | 2019 | PMID: 30710474 |
| Analysis of publicly available LDLR, APOB, and PCSK9 variants associated with familial hypercholesterolemia: application of ACMG guidelines and implications for familial hypercholesterolemia diagnosis. | Chora JR | Genetics in medicine : official journal of the American College of Medical Genetics | 2018 | PMID: 29261184 |
| Spectrum of mutations in Italian patients with familial hypercholesterolemia: New results from the LIPIGEN study. | Pirillo A | Atherosclerosis. Supplements | 2017 | PMID: 28965616 |
| The Proprotein Convertase Subtilisin/Kexin Type 9-resistant R410S Low Density Lipoprotein Receptor Mutation: A NOVEL MECHANISM CAUSING FAMILIAL HYPERCHOLESTEROLEMIA. | Susan-Resiga D | The Journal of biological chemistry | 2017 | PMID: 27998977 |
| The molecular genetic background of familial hypercholesterolemia: data from the Slovak nation-wide survey. | Gabčová D | Physiological research | 2017 | PMID: 27824480 |
| Individual analysis of patients with HoFH participating in a phase 3 trial with lomitapide: The Italian cohort. | Averna M | Nutrition, metabolism, and cardiovascular diseases : NMCD | 2016 | PMID: 26723464 |
| Systematic analysis of variants related to familial hypercholesterolemia in families with premature myocardial infarction. | Brænne I | European journal of human genetics : EJHG | 2016 | PMID: 26036859 |
| Mutational analysis of a cohort with clinical diagnosis of familial hypercholesterolemia: considerations for genetic diagnosis improvement. | Medeiros AM | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 26020417 |
| Molecular-genetic aspects of familial hypercholesterolemia. | Gabcova-Balaziova D | Endocrine regulations | 2015 | PMID: 26238499 |
| Pregnancy in homozygous familial hypercholesterolemia--Importance of LDL-apheresis. | Blaha M | Atherosclerosis. Supplements | 2015 | PMID: 25936317 |
| Systematic cell-based phenotyping of missense alleles empowers rare variant association studies: a case for LDLR and myocardial infarction. | Thormaehlen AS | PLoS genetics | 2015 | PMID: 25647241 |
| Actionable exomic incidental findings in 6503 participants: challenges of variant classification. | Amendola LM | Genome research | 2015 | PMID: 25637381 |
| Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. | Do R | Nature | 2015 | PMID: 25487149 |
| Familial hypercholesterolemia in Brazil: cascade screening program, clinical and genetic aspects. | Jannes CE | Atherosclerosis | 2015 | PMID: 25461735 |
| Familial Hypercholesterolemia in Greek children and their families: genotype-to-phenotype correlations and a reconsideration of LDLR mutation spectrum. | Mollaki V | Atherosclerosis | 2014 | PMID: 25463123 |
| Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol. | Lange LA | American journal of human genetics | 2014 | PMID: 24507775 |
| Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy. | Bertolini S | Atherosclerosis | 2013 | PMID: 23375686 |
| The molecular basis of familial hypercholesterolemia in the Czech Republic: spectrum of LDLR mutations and genotype-phenotype correlations. | Tichý L | Atherosclerosis | 2012 | PMID: 22698793 |
| Cardiovascular risk in relation to functionality of sequence variants in the gene coding for the low-density lipoprotein receptor: a study among 29,365 individuals tested for 64 specific low-density lipoprotein-receptor sequence variants. | Huijgen R | European heart journal | 2012 | PMID: 22390909 |
| Spectrum of LDLR gene mutations, including a novel mutation causing familial hypercholesterolaemia, in North-western Greece. | Diakou M | European journal of internal medicine | 2011 | PMID: 21925044 |
| An improved method on stimulated T-lymphocytes to functionally characterize novel and known LDLR mutations. | Romano M | Journal of lipid research | 2011 | PMID: 21865347 |
| An APEX-based genotyping microarray for the screening of 168 mutations associated with familial hypercholesterolemia. | Dušková L | Atherosclerosis | 2011 | PMID: 21310417 |
| Genomic characterization of large rearrangements of the LDLR gene in Czech patients with familial hypercholesterolemia. | Goldmann R | BMC medical genetics | 2010 | PMID: 20663204 |
| Functionality of sequence variants in the genes coding for the low-density lipoprotein receptor and apolipoprotein B in individuals with inherited hypercholesterolemia. | Huijgen R | Human mutation | 2010 | PMID: 20506408 |
| Molecular characterization of Polish patients with familial hypercholesterolemia: novel and recurrent LDLR mutations. | Chmara M | Journal of applied genetics | 2010 | PMID: 20145306 |
| The type of LDLR gene mutation predicts cardiovascular risk in children with familial hypercholesterolemia. | Guardamagna O | The Journal of pediatrics | 2009 | PMID: 19446849 |
| Evaluation of high-resolution melting analysis for screening the LDL receptor gene. | Laurie AD | Clinical biochemistry | 2009 | PMID: 19118540 |
| Longitudinal evaluation and assessment of cardiovascular disease in patients with homozygous familial hypercholesterolemia. | Kolansky DM | The American journal of cardiology | 2008 | PMID: 19026292 |
| Clinical course of homozygous familial hypercholesterolemia during childhood: report on 4 unrelated patients with homozygous or compound heterozygous mutations in the LDLR gene. | Kubalska J | Journal of applied genetics | 2008 | PMID: 18263977 |
| Development of a universal chemiluminometric genotyping method for high-throughput detection of 7 LDLR gene mutations in Greek population. | Glynou K | Clinical biochemistry | 2008 | PMID: 18206115 |
| Familial hypercholesterolaemia in Portugal. | Bourbon M | Atherosclerosis | 2008 | PMID: 17765246 |
| Detection of familial hypercholesterolemia in a cohort of children with hypercholesterolemia: results of a family and DNA-based screening. | Campagna F | Atherosclerosis | 2008 | PMID: 17196209 |
| Multiplex ARMS analysis to detect 13 common mutations in familial hypercholesterolaemia. | Taylor A | Clinical genetics | 2007 | PMID: 17539906 |
| A rare polymorphism in the low density lipoprotein (LDL) gene that affects mRNA splicing. | Bourbon M | Atherosclerosis | 2007 | PMID: 17335829 |
| Genetic and environmental factors affecting the response to statin therapy in patients with molecularly defined familial hypercholesterolaemia. | Miltiadous G | Pharmacogenetics and genomics | 2005 | PMID: 15864114 |
| Molecular characterization of familial hypercholesterolemia in Spain: identification of 39 novel and 77 recurrent mutations in LDLR. | Mozas P | Human mutation | 2004 | PMID: 15241806 |
| Application of molecular genetics for diagnosing familial hypercholesterolemia in Norway: results from a family-based screening program. | Leren TP | Seminars in vascular medicine | 2004 | PMID: 15199436 |
| Spectrum of low density lipoprotein receptor mutations in Czech hypercholesterolemic patients. | Kuhrová V | Human mutation | 2002 | PMID: 11754108 |
| [Identification of novel missense mutation G571E, novel silent mutation H229H, nonsense mutation C74X, and four single nucleotide polymorphisms in the low-density lipoprotein receptor in patients with familial hypercholesterolemia from St. Petersburg]. | Zakharova FM | Bioorganicheskaia khimiia | 2001 | PMID: 11641914 |
| Characterization and geographic distribution of the low density lipoprotein receptor (LDLR) gene mutations in northwestern Greece. | Miltiadous G | Human mutation | 2001 | PMID: 11317361 |
| Eight novel LDL receptor gene mutations among patients under LDL apheresis in Dresden and Leipzig. | Bochmann H | Human mutation | 2001 | PMID: 11139254 |
| Analysis of LDL receptor gene mutations in Italian patients with homozygous familial hypercholesterolemia. | Bertolini S | Arteriosclerosis, thrombosis, and vascular biology | 1999 | PMID: 9974426 |
| LDL-R and Apo-B-100 gene mutations in Polish familial hypercholesterolemias. | Górski B | Human genetics | 1998 | PMID: 9654205 |
| Molecular genetics of the LDL receptor gene in familial hypercholesterolemia. | Hobbs HH | Human mutation | 1992 | PMID: 1301956 |
| https://erepo.clinicalgenome.org/evrepo/ui/interpretation/cd0c4aea-7158-4181-83f0-1c4cce449e45 | - | - | - | - |
| https://www.ncbi.nlm.nih.gov/clinvar/variation/161271/ | - | - | - | - |
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Text-mined citations for rs137929307 ...
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Record last updated Jul 06, 2026
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.