Variant summary: The c.1201C>G variant affects a conserved nucleotide, resulting in amino acid change from Leu to Val. 3/4 in-silico tools predict this variant to be damaging (SNPs&GO not captured due to low reliability index). This variant is found in 2/119858 control chromosomes at a frequency of 0.0000167, which does not exceed maximal expected frequency of a pathogenic allele (0.0012508) to exclude pathogenicity. The variant was reported in several FH patients and one study reported the variant to co-segregate with hypercholesterolemia (Leren_JIM_19970) indicating pathogenicity. In addition, a clinical laboratory and a reputable database classify this variant as Likely pathogenic / Disease causing. Taken together, this variant was classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.1201C>G (p.Leu401Val)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(18)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
18
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000527.5(LDLR):c.1201C>G (p.Leu401Val)
Variation ID: 161267 Accession: VCV000161267.32
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 19p13.2 19: 11113292 (GRCh38) [ NCBI UCSC ] 19: 11223968 (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 Jan 19, 2025 May 24, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000527.5:c.1201C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000518.1:p.Leu401Val missense NM_001195798.2:c.1201C>G NP_001182727.1:p.Leu401Val missense NM_001195799.2:c.1078C>G NP_001182728.1:p.Leu360Val missense NM_001195800.2:c.697C>G NP_001182729.1:p.Leu233Val missense NM_001195803.2:c.820C>G NP_001182732.1:p.Leu274Val missense NC_000019.10:g.11113292C>G NC_000019.9:g.11223968C>G NG_009060.1:g.28912C>G LRG_274:g.28912C>G LRG_274t1:c.1201C>G LRG_274p1:p.Leu401Val P01130:p.Leu401Val - Protein change
- L401V, L233V, L274V, L360V
- Other names
- -
- Canonical SPDI
- NC_000019.10:11113291:C:G
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
- 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 |
4132 | 4422 | |
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. |
|---|---|---|---|---|
| Likely pathogenic (9) |
criteria provided, multiple submitters, no conflicts
|
Nov 14, 2023 | RCV000238417.26 | |
| Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
May 24, 2024 | RCV000255176.14 | |
| Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Jan 11, 2024 | RCV000586642.20 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
Jun 1, 2014 | RCV002051660.10 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Jul 16, 2021 | RCV002345455.9 |
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. |
More information
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. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Mar 25, 2016)
|
criteria provided, single submitter
Method: literature only
|
Familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
LDLR-LOVD, British Heart Foundation
Accession: SCV000295293.2
First in ClinVar: Jul 29, 2016 Last updated: May 19, 2018 |
Observation 1:
Number of individuals with the variant: 1
Observation 2:
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Apr 28, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000697189.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The c.1201C>G variant affects a conserved nucleotide, resulting in amino acid change from Leu to Val. 3/4 in-silico tools predict this variant to … (more)
Variant summary: The c.1201C>G variant affects a conserved nucleotide, resulting in amino acid change from Leu to Val. 3/4 in-silico tools predict this variant to be damaging (SNPs&GO not captured due to low reliability index). This variant is found in 2/119858 control chromosomes at a frequency of 0.0000167, which does not exceed maximal expected frequency of a pathogenic allele (0.0012508) to exclude pathogenicity. The variant was reported in several FH patients and one study reported the variant to co-segregate with hypercholesterolemia (Leren_JIM_19970) indicating pathogenicity. In addition, a clinical laboratory and a reputable database classify this variant as Likely pathogenic / Disease causing. Taken together, this variant was classified as Pathogenic. (less)
|
|
|
Likely pathogenic
(May 11, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
Affected status: unknown
Allele origin:
germline
|
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV000839994.1
First in ClinVar: May 19, 2018 Last updated: May 19, 2018 |
Comment:
The c.1201C>G (p.Leu401Val) variant in the LDLR gene has been observed in multiple individuals with familial hypercholesteromeia (PMID: 9104431, 21722902, 25461735). In addition, a missense … (more)
The c.1201C>G (p.Leu401Val) variant in the LDLR gene has been observed in multiple individuals with familial hypercholesteromeia (PMID: 9104431, 21722902, 25461735). In addition, a missense variant at the same residue, p.Leu401His, has been previously reported in other affected individuals (PMID: 7573037, 11810272,15701167). Therefore, this variant in the LDLR gene is classified as likely pathogenic. (less)
|
|
|
Likely pathogenic
(Aug 05, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV001347900.2
First in ClinVar: Jun 22, 2020 Last updated: Jun 19, 2021 |
Comment:
This missense variant (also known as p.Leu380Val in the mature protein) replaces leucine with valine at codon 401 of the LDLR protein. Computational prediction suggests … (more)
This missense variant (also known as p.Leu380Val in the mature protein) replaces leucine with valine at codon 401 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). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 9104431, 21722902, 25461735, 32715071) and segregated with disease in multiple families (PMID: 9104431). This variant has been identified in 7/282282 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. (less)
|
|
|
Likely pathogenic
(Mar 06, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
Affected status: unknown
Allele origin:
germline
|
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV003932178.1
First in ClinVar: Jun 17, 2023 Last updated: Jun 17, 2023 |
Comment:
PS3_Moderate, PM2, PM5_Supporting, PP3
Secondary finding: yes
|
|
|
Likely pathogenic
(Aug 31, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002022661.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Likely Pathogenic
(Nov 14, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
(Semidominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004820276.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 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:
This missense variant (also known as p.Leu380Val in the mature protein) replaces leucine with valine at codon 401 of the LDLR protein. Computational prediction suggests … (more)
This missense variant (also known as p.Leu380Val in the mature protein) replaces leucine with valine at codon 401 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). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 9104431, 21722902, 25461735, 32715071) and segregated with disease in multiple families (PMID: 9104431). This variant has been identified in 7/282282 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. (less)
Number of individuals with the variant: 1
Zygosity: Single Heterozygote
|
|
|
Likely pathogenic
(Jul 16, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002650517.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.L401V variant (also known as c.1201C>G), located in coding exon 9 of the LDLR gene, results from a C to G substitution at nucleotide … (more)
The p.L401V variant (also known as c.1201C>G), located in coding exon 9 of the LDLR gene, results from a C to G substitution at nucleotide position 1201. The leucine at codon 401 is replaced by valine, an amino acid with highly similar properties. This alteration, also referred to as L380V, has been reported in hypercholesterolemia and early onset myocardial infarction cohorts (Leren TP et al. J. Intern. Med., 1997 Mar;241:185-94; Vaca G et al. Atherosclerosis, 2011 Oct;218:391-6; Lange LA et al. Am. J. Hum. Genet., 2014 Feb;94:233-45; Jannes CE et al. Atherosclerosis, 2015 Jan;238:101-7; Khera AV et al. Circulation, 2019 03;139:1593-1602). This alteration was also described to segregate with the disease (Leren TP et al. J. Intern. Med., 1997 Mar;241:185-94). This variant has been seen in an exome cohort, but cardiovascular history was not provided (Amendola LM et al. Genome Res., 2015 Mar;25:305-15). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
|
|
|
likely pathogenic
(Mar 11, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV004219938.2
First in ClinVar: Jan 06, 2024 Last updated: Jan 19, 2025 |
Comment:
The LDLR c.1201C>G (p.Leu401Val) variant has been reported in the published literature in individuals with familial hypercholesterolemia (FH) (PMID: 9104431 (1997), 21722902 (2011), 25461735 (2015), … (more)
The LDLR c.1201C>G (p.Leu401Val) variant has been reported in the published literature in individuals with familial hypercholesterolemia (FH) (PMID: 9104431 (1997), 21722902 (2011), 25461735 (2015), 32715071(2020), 34037665 (2021), 33740630 (2021)). The frequency of this variant in the general population, 0.0002 (5/24928 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic. (less)
|
|
|
Likely pathogenic
(Nov 02, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: yes
Allele origin:
germline
|
AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002502785.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Secondary finding: no
|
|
|
Pathogenic
(Jan 11, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000627015.6
First in ClinVar: Dec 26, 2017 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 401 of the LDLR protein (p.Leu401Val). … (more)
This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 401 of the LDLR protein (p.Leu401Val). This variant is present in population databases (rs146200173, gnomAD 0.02%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 9104431, 12124988, 21722902, 24507775, 25461735). This variant is also known as p.Leu380Val. ClinVar contains an entry for this variant (Variation ID: 161267). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. This variant disrupts the p.Leu401 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7573037, 11810272, 15701167, 19843101). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Likely pathogenic
(May 24, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000322301.11
First in ClinVar: Oct 09, 2016 Last updated: Sep 16, 2024 |
Comment:
Reported in individuals with a history of early-onset myocardial infarction (PMID: 30586733); In silico analysis supports that this missense variant has a deleterious effect on … (more)
Reported in individuals with a history of early-onset myocardial infarction (PMID: 30586733); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(L380V); This variant is associated with the following publications: (PMID: 12124988, 25461735, 32041611, 32715071, 33740630, 25637381, 23669246, 21722902, 24507775, 23833242, 31447099, 34037665, 34040191, 33955087, 22683370, 21957200, 9104431, 30586733) (less)
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: research
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum
Accession: SCV000606356.1
First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
|
|
|
Pathogenic
(Jan 22, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002086413.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
|
|
Likely pathogenic
(Jun 01, 2014)
|
no assertion criteria provided
Method: research
|
Hypercholesterolaemia
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
CSER _CC_NCGL, University of Washington
Study: ESP 6500 variant annotation
Accession: SCV000190285.1 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
|
|
|
|
Uncertain significance
(Mar 01, 2016)
|
Flagged submission
flagged submission
Method: research
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Iberoamerican FH Network
Accession: SCV000748051.1
First in ClinVar: May 19, 2018 Last updated: May 19, 2018
Comment:
Variant present in the databases from Mexico and Uruguay
|
Comment on evidence:
%MAF(ExAC):0.001669
|
|
|
Uncertain significance
(Dec 16, 2016)
|
Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
|
Hypercholesterolemia, familial, 1
Affected status: yes
Allele origin:
germline
|
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix
Accession: SCV000503313.1
First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016 |
Comment:
subject mutated among 2600 FH index cases screened = 1 compound heterozygous on LDL Apheresis /FH-Norvege / Software predictions: Conflicting
Number of individuals with the variant: 1
|
|
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Uncertain significance
(Mar 01, 2016)
|
Flagged submission
flagged submission
Method: research
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Laboratory of Genetics and Molecular Cardiology, University of São Paulo
Study: HipercolBrasil
Accession: SCV000588564.1 First in ClinVar: Aug 13, 2017 Last updated: Aug 13, 2017 |
Comment on evidence:
%MAF(ExAC):0.001669
|
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| click to load more click to collapse | |||||
| Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more | |||||
Comment:
Comment:
The c.1201C>G (p.Leu401Val) variant in the LDLR gene has been observed in multiple individuals with familial hypercholesteromeia (PMID: 9104431, 21722902, 25461735). In addition, a missense variant at the same residue, p.Leu401His, has been previously reported in other affected individuals (PMID: 7573037, 11810272,15701167). Therefore, this variant in the LDLR gene is classified as likely pathogenic.
Comment:
This missense variant (also known as p.Leu380Val in the mature protein) replaces leucine with valine at codon 401 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). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 9104431, 21722902, 25461735, 32715071) and segregated with disease in multiple families (PMID: 9104431). This variant has been identified in 7/282282 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Comment:
PS3_Moderate, PM2, PM5_Supporting, PP3
Comment:
This missense variant (also known as p.Leu380Val in the mature protein) replaces leucine with valine at codon 401 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). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 9104431, 21722902, 25461735, 32715071) and segregated with disease in multiple families (PMID: 9104431). This variant has been identified in 7/282282 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Comment:
The p.L401V variant (also known as c.1201C>G), located in coding exon 9 of the LDLR gene, results from a C to G substitution at nucleotide position 1201. The leucine at codon 401 is replaced by valine, an amino acid with highly similar properties. This alteration, also referred to as L380V, has been reported in hypercholesterolemia and early onset myocardial infarction cohorts (Leren TP et al. J. Intern. Med., 1997 Mar;241:185-94; Vaca G et al. Atherosclerosis, 2011 Oct;218:391-6; Lange LA et al. Am. J. Hum. Genet., 2014 Feb;94:233-45; Jannes CE et al. Atherosclerosis, 2015 Jan;238:101-7; Khera AV et al. Circulation, 2019 03;139:1593-1602). This alteration was also described to segregate with the disease (Leren TP et al. J. Intern. Med., 1997 Mar;241:185-94). This variant has been seen in an exome cohort, but cardiovascular history was not provided (Amendola LM et al. Genome Res., 2015 Mar;25:305-15). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Comment:
The LDLR c.1201C>G (p.Leu401Val) variant has been reported in the published literature in individuals with familial hypercholesterolemia (FH) (PMID: 9104431 (1997), 21722902 (2011), 25461735 (2015), 32715071(2020), 34037665 (2021), 33740630 (2021)). The frequency of this variant in the general population, 0.0002 (5/24928 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic.
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 401 of the LDLR protein (p.Leu401Val). This variant is present in population databases (rs146200173, gnomAD 0.02%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 9104431, 12124988, 21722902, 24507775, 25461735). This variant is also known as p.Leu380Val. ClinVar contains an entry for this variant (Variation ID: 161267). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. This variant disrupts the p.Leu401 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7573037, 11810272, 15701167, 19843101). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
Reported in individuals with a history of early-onset myocardial infarction (PMID: 30586733); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(L380V); This variant is associated with the following publications: (PMID: 12124988, 25461735, 32041611, 32715071, 33740630, 25637381, 23669246, 21722902, 24507775, 23833242, 31447099, 34037665, 34040191, 33955087, 22683370, 21957200, 9104431, 30586733)
Comment:
subject mutated among 2600 FH index cases screened = 1 compound heterozygous on LDL Apheresis /FH-Norvege / Software predictions: Conflicting
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
Variant summary: The c.1201C>G variant affects a conserved nucleotide, resulting in amino acid change from Leu to Val. 3/4 in-silico tools predict this variant to be damaging (SNPs&GO not captured due to low reliability index). This variant is found in 2/119858 control chromosomes at a frequency of 0.0000167, which does not exceed maximal expected frequency of a pathogenic allele (0.0012508) to exclude pathogenicity. The variant was reported in several FH patients and one study reported the variant to co-segregate with hypercholesterolemia (Leren_JIM_19970) indicating pathogenicity. In addition, a clinical laboratory and a reputable database classify this variant as Likely pathogenic / Disease causing. Taken together, this variant was classified as Pathogenic.
Comment:
The c.1201C>G (p.Leu401Val) variant in the LDLR gene has been observed in multiple individuals with familial hypercholesteromeia (PMID: 9104431, 21722902, 25461735). In addition, a missense variant at the same residue, p.Leu401His, has been previously reported in other affected individuals (PMID: 7573037, 11810272,15701167). Therefore, this variant in the LDLR gene is classified as likely pathogenic.
Comment:
This missense variant (also known as p.Leu380Val in the mature protein) replaces leucine with valine at codon 401 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). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 9104431, 21722902, 25461735, 32715071) and segregated with disease in multiple families (PMID: 9104431). This variant has been identified in 7/282282 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Comment:
PS3_Moderate, PM2, PM5_Supporting, PP3
Comment:
This missense variant (also known as p.Leu380Val in the mature protein) replaces leucine with valine at codon 401 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). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 9104431, 21722902, 25461735, 32715071) and segregated with disease in multiple families (PMID: 9104431). This variant has been identified in 7/282282 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Comment:
The p.L401V variant (also known as c.1201C>G), located in coding exon 9 of the LDLR gene, results from a C to G substitution at nucleotide position 1201. The leucine at codon 401 is replaced by valine, an amino acid with highly similar properties. This alteration, also referred to as L380V, has been reported in hypercholesterolemia and early onset myocardial infarction cohorts (Leren TP et al. J. Intern. Med., 1997 Mar;241:185-94; Vaca G et al. Atherosclerosis, 2011 Oct;218:391-6; Lange LA et al. Am. J. Hum. Genet., 2014 Feb;94:233-45; Jannes CE et al. Atherosclerosis, 2015 Jan;238:101-7; Khera AV et al. Circulation, 2019 03;139:1593-1602). This alteration was also described to segregate with the disease (Leren TP et al. J. Intern. Med., 1997 Mar;241:185-94). This variant has been seen in an exome cohort, but cardiovascular history was not provided (Amendola LM et al. Genome Res., 2015 Mar;25:305-15). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Comment:
The LDLR c.1201C>G (p.Leu401Val) variant has been reported in the published literature in individuals with familial hypercholesterolemia (FH) (PMID: 9104431 (1997), 21722902 (2011), 25461735 (2015), 32715071(2020), 34037665 (2021), 33740630 (2021)). The frequency of this variant in the general population, 0.0002 (5/24928 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic.
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 401 of the LDLR protein (p.Leu401Val). This variant is present in population databases (rs146200173, gnomAD 0.02%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 9104431, 12124988, 21722902, 24507775, 25461735). This variant is also known as p.Leu380Val. ClinVar contains an entry for this variant (Variation ID: 161267). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. This variant disrupts the p.Leu401 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7573037, 11810272, 15701167, 19843101). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
Reported in individuals with a history of early-onset myocardial infarction (PMID: 30586733); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(L380V); This variant is associated with the following publications: (PMID: 12124988, 25461735, 32041611, 32715071, 33740630, 25637381, 23669246, 21722902, 24507775, 23833242, 31447099, 34037665, 34040191, 33955087, 22683370, 21957200, 9104431, 30586733)
Comment:
subject mutated among 2600 FH index cases screened = 1 compound heterozygous on LDL Apheresis /FH-Norvege / Software predictions: Conflicting
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Limited-Variant Screening vs Comprehensive Genetic Testing for Familial Hypercholesterolemia Diagnosis. | Sturm AC | JAMA cardiology | 2021 | PMID: 34037665 |
| 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 |
| Xanthomas heralding pediatric coronary artery disease. | Edelman A | JAAD case reports | 2020 | PMID: 32715071 |
| 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 |
| 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 |
| Whole-Genome Sequencing to Characterize Monogenic and Polygenic Contributions in Patients Hospitalized With Early-Onset Myocardial Infarction. | Khera AV | Circulation | 2019 | PMID: 30586733 |
| Actionable exomic incidental findings in 6503 participants: challenges of variant classification. | Amendola LM | Genome research | 2015 | PMID: 25637381 |
| Familial hypercholesterolemia in Brazil: cascade screening program, clinical and genetic aspects. | Jannes CE | Atherosclerosis | 2015 | PMID: 25461735 |
| Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol. | Lange LA | American journal of human genetics | 2014 | PMID: 24507775 |
| Inheritance pattern of familial hypercholesterolemia and markers of cardiovascular risk. | Kusters DM | Journal of lipid research | 2013 | PMID: 23833242 |
| Analysis of the frequency and spectrum of mutations recognised to cause familial hypercholesterolaemia in routine clinical practice in a UK specialist hospital lipid clinic. | Futema M | Atherosclerosis | 2013 | PMID: 23669246 |
| Serum levels of proprotein convertase subtilisin/kexin type 9 in subjects with familial hypercholesterolemia indicate that proprotein convertase subtilisin/kexin type 9 is cleared from plasma by low-density lipoprotein receptor-independent pathways. | Cameron J | Translational research : the journal of laboratory and clinical medicine | 2012 | PMID: 22683370 |
| LDL-apheresis depletes apoE-HDL and pre-β1-HDL in familial hypercholesterolemia: relevance to atheroprotection. | Orsoni A | Journal of lipid research | 2011 | PMID: 21957200 |
| Mutational analysis of the LDL receptor and APOB genes in Mexican individuals with autosomal dominant hypercholesterolemia. | Vaca G | Atherosclerosis | 2011 | PMID: 21722902 |
| Mutation screening in patients for familial hypercholesterolaemia (ADH). | Taylor A | Clinical genetics | 2010 | PMID: 19843101 |
| Familial hypercholesterolemia in St-Petersburg: the known and novel mutations found in the low density lipoprotein receptor gene in Russia. | Zakharova FM | BMC medical genetics | 2005 | PMID: 15701167 |
| The UMD-LDLR database: additions to the software and 490 new entries to the database. | Villéger L | Human mutation | 2002 | PMID: 12124988 |
| The molecular basis of familial hypercholesterolemia in The Netherlands. | Fouchier SW | Human genetics | 2001 | PMID: 11810272 |
| Mutant transcripts of the LDL receptor gene: mRNA structure and quantity. | Rødningen OK | Human mutation | 1999 | PMID: 10090473 |
| Molecular genetics of familial hypercholesterolaemia in Norway. | Leren TP | Journal of internal medicine | 1997 | PMID: 9104431 |
| Molecular characterization of minor gene rearrangements in Finnish patients with heterozygous familial hypercholesterolemia: identification of two common missense mutations (Gly823-->Asp and Leu380-->His) and eight rare mutations of the LDL receptor gene. | Koivisto UM | American journal of human genetics | 1995 | PMID: 7573037 |
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Text-mined citations for this variant ...
HelpRecord last updated Jan 19, 2025
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.