Identified in patients with familial hypercholesterolemia in published literature, although segregation data is largely unavailable (PMID: 9544745, 11313767, 17539906, 17094996, 20145306, 21310417, 23054246, 22883975, 24075752, 24956927, 25487149, 12459547, 2988123); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(C88Y); This variant is associated with the following publications: (PMID: 25487149, 17094996, 20145306, 19837725, 21310417, 24075752, 17539906, 22883975, 23054246, 11313767, 9544745, 9409298, 33740630, 33418990, 34037665, 32041611, 24956927, 12459547, 2988123)
ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.326G>A (p.Cys109Tyr)
Germline
Classification
Help
criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.
Pathogenic/Likely pathogenic
9 out of 11 submissions contributed to this 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.
11
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000527.5(LDLR):c.326G>A (p.Cys109Tyr)
Variation ID: 226319 Accession: VCV000226319.23
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 19p13.2 19: 11105232 (GRCh38) [ NCBI UCSC ] 19: 11215908 (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 May 22, 2016 Feb 25, 2025 Jun 11, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000527.5:c.326G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000518.1:p.Cys109Tyr missense NM_001195798.2:c.326G>A NP_001182727.1:p.Cys109Tyr missense NM_001195799.2:c.203G>A NP_001182728.1:p.Cys68Tyr missense NM_001195800.2:c.314-2160G>A intron variant NM_001195803.2:c.314-1333G>A intron variant NC_000019.10:g.11105232G>A NC_000019.9:g.11215908G>A NG_009060.1:g.20852G>A LRG_274:g.20852G>A LRG_274t1:c.326G>A LRG_274p1:p.Cys109Tyr - Protein change
- C109Y, C68Y
- Other names
-
NP_000518.1:p.C109Y
- Canonical SPDI
- NC_000019.10:11105231:G:A
-
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.
-
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
- 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 |
4260 | 4567 | |
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/Likely pathogenic (7) |
criteria provided, multiple submitters, no conflicts
|
Apr 25, 2024 | RCV000211658.12 | |
| Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jun 11, 2024 | RCV000521830.5 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Oct 28, 2023 | RCV000820331.7 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Apr 24, 2024 | RCV002444847.3 |
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)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: literature only
|
Familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
LDLR-LOVD, British Heart Foundation
Accession: SCV000294631.2
First in ClinVar: Jul 29, 2016 Last updated: May 30, 2018 |
Observation 1:
Number of individuals with the variant: 1
Observation 2:
Number of individuals with the variant: 1
Observation 3:
Number of individuals with the variant: 1
Observation 4:
Number of individuals with the variant: 1
|
|
|
Likely pathogenic
(-)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Robarts Research Institute, Western University
Accession: SCV000484762.1
First in ClinVar: Dec 17, 2016 Last updated: Dec 17, 2016 |
Number of individuals with the variant: 1
|
|
|
Likely pathogenic
(Jun 11, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000617501.3
First in ClinVar: Dec 19, 2017 Last updated: Sep 16, 2024 |
Comment:
Identified in patients with familial hypercholesterolemia in published literature, although segregation data is largely unavailable (PMID: 9544745, 11313767, 17539906, 17094996, 20145306, 21310417, 23054246, 22883975, 24075752, … (more)
Identified in patients with familial hypercholesterolemia in published literature, although segregation data is largely unavailable (PMID: 9544745, 11313767, 17539906, 17094996, 20145306, 21310417, 23054246, 22883975, 24075752, 24956927, 25487149, 12459547, 2988123); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(C88Y); This variant is associated with the following publications: (PMID: 25487149, 17094996, 20145306, 19837725, 21310417, 24075752, 17539906, 22883975, 23054246, 11313767, 9544745, 9409298, 33740630, 33418990, 34037665, 32041611, 24956927, 12459547, 2988123) (less)
|
|
|
Likely pathogenic
(Apr 24, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002612497.3
First in ClinVar: Nov 29, 2022 Last updated: Aug 11, 2024 |
Comment:
The c.326G>A (p.C109Y) alteration is located in exon 4 (coding exon 4) of the LDLR gene. This alteration results from a G to A substitution … (more)
The c.326G>A (p.C109Y) alteration is located in exon 4 (coding exon 4) of the LDLR gene. This alteration results from a G to A substitution at nucleotide position 326, causing the cysteine (C) at amino acid position 109 to be replaced by a tyrosine (Y). Based on data from gnomAD, the A allele has an overall frequency of <0.001% (1/250250) total alleles studied. The highest observed frequency was 0.001% (1/112912) of European (non-Finnish) alleles. This alteration, which is also known at p.C88Y, has been reported in individuals with FH (Sun, 1998; Heath, 2001; Sozen, 2004; Taylor, 2007; Chmara, 2010; Hooper, 2012; Norsworthy, 2014; Do, 2015; Dron, 2020; Meshkov, 2021; Sturm, 2021; Leren, 2021). This amino acid position is highly conserved in available vertebrate species. Pathogenic LDLR mutations that result in the substitution or generation of cysteine residues within the cysteine-rich LDLR class A repeats and EGF-like domains are common in familial hypercholesterolemia (FH) (Villéger, 2002). Internal structural analysis indicates this variant eliminates a disulfide bond critical for the structural integrity of the LDLR class A repeat 3 domain (Ambry internal data). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. (less)
|
|
|
Pathogenic
(Oct 28, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000961039.7
First in ClinVar: Aug 14, 2019 Last updated: Feb 25, 2025 |
Comment:
This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 109 of the LDLR protein … (more)
This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 109 of the LDLR protein (p.Cys109Tyr). This variant is present in population databases (rs121908042, gnomAD 0.0009%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 9544745, 11313767, 20145306, 21310417, 22883975, 24956927). This variant is also known as Cys88Tyr. ClinVar contains an entry for this variant (Variation ID: 226319). 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 affects a cysteine residue located within an LDLRA or epidermal-growth-factor (EGF)-like domains of the LDLR protein. Cysteine residues in these domains have been shown to be involved in the formation of disulfide bridges, which are critical for protein structure and stability (PMID: 7548065, 7603991, 7979249). In addition, missense substitutions within the LDLRA and EGF-like domains affecting cysteine residues are overrepresented among patients with hypercholesterolemia (PMID: 18325082). This variant disrupts the p.Cys109 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 11313767, 12009418), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Oct 01, 2021)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
Affected status: yes
Allele origin:
germline
|
Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004175578.1
First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023 |
|
|
|
Pathogenic
(Feb 07, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV004219981.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
The frequency of this variant in the general population, 0.000004 (1/250250 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the … (more)
The frequency of this variant in the general population, 0.000004 (1/250250 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with familial hypercholesterolemia (FH) (PMID: 9544745 (1998), 11313767 (2001), 16465405 (2006), 21310417 (2011), 22883975 (2012), 23054246 (2012), 33418990 (2021)), including one compound heterozygous individual (PMID: 22883975 (2012)). It was also reported in individuals with autosomal dominant hypercholesterolemia (PMID: 20145306 (2010), 33740630 (2021)), and coronary artery disease (PMID: 27050191 (2016)). 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 pathogenic. (less)
|
|
|
Pathogenic
(-)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
Affected status: yes
Allele origin:
germline
|
Juno Genomics, Hangzhou Juno Genomics, Inc
Accession: SCV005417140.1
First in ClinVar: Nov 30, 2024 Last updated: Nov 30, 2024 |
Comment:
PM2_Supporting+PS4_Moderate+PP4+PM1+PP3_Strong
|
|
|
Pathogenic
(Apr 25, 2024)
C
Contributing to aggregate classification
|
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: SCV005426440.1
First in ClinVar: Dec 14, 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:
This missense variant (also known as p.Cys88Tyr in the mature protein) replaces cysteine with tyrosine at codon 109 in the LDLR type A repeat 3 … (more)
This missense variant (also known as p.Cys88Tyr in the mature protein) replaces cysteine with tyrosine at codon 109 in the LDLR type A repeat 3 of the LDLR protein. This variant alters a conserved cysteine residue that is critical for proper protein folding and function (PMID: 2088165, 6091915, 15952897). Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This LDLR variant has been reported in over 10 heterozygous individuals affected with familial hypercholesterolemia (PMID: 9026534, 11313767, 17094996, 17539906, 20145306, 22883975, 23833242, 24075752, 33418990, 33740630, 34037665). This variant has also been observed in compound heterozygous state with a known pathogenic LDLR variant in an individual affected with severe homozygous familial hypercholesterolemia and extensive atherosclerotic cardiovascular disease, a phenotype expected of having two deleterious LDLR variants (PMID: 22883975, 32276786). Additionally, this variant has been reported in an individual affected with coronary artery disease (PMID: 27050191) and in an individual affected with moderately high total cholesterol despite cholesterol-lowering therapy (PMID: 24956927). This variant has been identified in 1/250250 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less)
Number of individuals with the variant: 1
Zygosity: Single Heterozygote
|
|
|
Pathogenic
(Jul 22, 2008)
N
Not contributing to aggregate classification
|
no assertion criteria provided
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: yes
Allele origin:
germline
|
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital
Accession: SCV000268557.1
First in ClinVar: May 22, 2016 Last updated: May 22, 2016 |
Number of individuals with the variant: 5
|
|
|
Pathogenic
(-)
N
Not contributing to aggregate classification
|
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: SCV000606087.1
First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
|
|
| click to load more submissions click to collapse | |||||
Comment:
Comment:
The c.326G>A (p.C109Y) alteration is located in exon 4 (coding exon 4) of the LDLR gene. This alteration results from a G to A substitution at nucleotide position 326, causing the cysteine (C) at amino acid position 109 to be replaced by a tyrosine (Y). Based on data from gnomAD, the A allele has an overall frequency of <0.001% (1/250250) total alleles studied. The highest observed frequency was 0.001% (1/112912) of European (non-Finnish) alleles. This alteration, which is also known at p.C88Y, has been reported in individuals with FH (Sun, 1998; Heath, 2001; Sozen, 2004; Taylor, 2007; Chmara, 2010; Hooper, 2012; Norsworthy, 2014; Do, 2015; Dron, 2020; Meshkov, 2021; Sturm, 2021; Leren, 2021). This amino acid position is highly conserved in available vertebrate species. Pathogenic LDLR mutations that result in the substitution or generation of cysteine residues within the cysteine-rich LDLR class A repeats and EGF-like domains are common in familial hypercholesterolemia (FH) (Villéger, 2002). Internal structural analysis indicates this variant eliminates a disulfide bond critical for the structural integrity of the LDLR class A repeat 3 domain (Ambry internal data). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.
Comment:
This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 109 of the LDLR protein (p.Cys109Tyr). This variant is present in population databases (rs121908042, gnomAD 0.0009%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 9544745, 11313767, 20145306, 21310417, 22883975, 24956927). This variant is also known as Cys88Tyr. ClinVar contains an entry for this variant (Variation ID: 226319). 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 affects a cysteine residue located within an LDLRA or epidermal-growth-factor (EGF)-like domains of the LDLR protein. Cysteine residues in these domains have been shown to be involved in the formation of disulfide bridges, which are critical for protein structure and stability (PMID: 7548065, 7603991, 7979249). In addition, missense substitutions within the LDLRA and EGF-like domains affecting cysteine residues are overrepresented among patients with hypercholesterolemia (PMID: 18325082). This variant disrupts the p.Cys109 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 11313767, 12009418), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Comment:
The frequency of this variant in the general population, 0.000004 (1/250250 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with familial hypercholesterolemia (FH) (PMID: 9544745 (1998), 11313767 (2001), 16465405 (2006), 21310417 (2011), 22883975 (2012), 23054246 (2012), 33418990 (2021)), including one compound heterozygous individual (PMID: 22883975 (2012)). It was also reported in individuals with autosomal dominant hypercholesterolemia (PMID: 20145306 (2010), 33740630 (2021)), and coronary artery disease (PMID: 27050191 (2016)). 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 pathogenic.
Comment:
PM2_Supporting+PS4_Moderate+PP4+PM1+PP3_Strong
Comment:
This missense variant (also known as p.Cys88Tyr in the mature protein) replaces cysteine with tyrosine at codon 109 in the LDLR type A repeat 3 of the LDLR protein. This variant alters a conserved cysteine residue that is critical for proper protein folding and function (PMID: 2088165, 6091915, 15952897). Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This LDLR variant has been reported in over 10 heterozygous individuals affected with familial hypercholesterolemia (PMID: 9026534, 11313767, 17094996, 17539906, 20145306, 22883975, 23833242, 24075752, 33418990, 33740630, 34037665). This variant has also been observed in compound heterozygous state with a known pathogenic LDLR variant in an individual affected with severe homozygous familial hypercholesterolemia and extensive atherosclerotic cardiovascular disease, a phenotype expected of having two deleterious LDLR variants (PMID: 22883975, 32276786). Additionally, this variant has been reported in an individual affected with coronary artery disease (PMID: 27050191) and in an individual affected with moderately high total cholesterol despite cholesterol-lowering therapy (PMID: 24956927). This variant has been identified in 1/250250 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
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:
Identified in patients with familial hypercholesterolemia in published literature, although segregation data is largely unavailable (PMID: 9544745, 11313767, 17539906, 17094996, 20145306, 21310417, 23054246, 22883975, 24075752, 24956927, 25487149, 12459547, 2988123); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(C88Y); This variant is associated with the following publications: (PMID: 25487149, 17094996, 20145306, 19837725, 21310417, 24075752, 17539906, 22883975, 23054246, 11313767, 9544745, 9409298, 33740630, 33418990, 34037665, 32041611, 24956927, 12459547, 2988123)
Comment:
The c.326G>A (p.C109Y) alteration is located in exon 4 (coding exon 4) of the LDLR gene. This alteration results from a G to A substitution at nucleotide position 326, causing the cysteine (C) at amino acid position 109 to be replaced by a tyrosine (Y). Based on data from gnomAD, the A allele has an overall frequency of <0.001% (1/250250) total alleles studied. The highest observed frequency was 0.001% (1/112912) of European (non-Finnish) alleles. This alteration, which is also known at p.C88Y, has been reported in individuals with FH (Sun, 1998; Heath, 2001; Sozen, 2004; Taylor, 2007; Chmara, 2010; Hooper, 2012; Norsworthy, 2014; Do, 2015; Dron, 2020; Meshkov, 2021; Sturm, 2021; Leren, 2021). This amino acid position is highly conserved in available vertebrate species. Pathogenic LDLR mutations that result in the substitution or generation of cysteine residues within the cysteine-rich LDLR class A repeats and EGF-like domains are common in familial hypercholesterolemia (FH) (Villéger, 2002). Internal structural analysis indicates this variant eliminates a disulfide bond critical for the structural integrity of the LDLR class A repeat 3 domain (Ambry internal data). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.
Comment:
This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 109 of the LDLR protein (p.Cys109Tyr). This variant is present in population databases (rs121908042, gnomAD 0.0009%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 9544745, 11313767, 20145306, 21310417, 22883975, 24956927). This variant is also known as Cys88Tyr. ClinVar contains an entry for this variant (Variation ID: 226319). 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 affects a cysteine residue located within an LDLRA or epidermal-growth-factor (EGF)-like domains of the LDLR protein. Cysteine residues in these domains have been shown to be involved in the formation of disulfide bridges, which are critical for protein structure and stability (PMID: 7548065, 7603991, 7979249). In addition, missense substitutions within the LDLRA and EGF-like domains affecting cysteine residues are overrepresented among patients with hypercholesterolemia (PMID: 18325082). This variant disrupts the p.Cys109 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 11313767, 12009418), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Comment:
The frequency of this variant in the general population, 0.000004 (1/250250 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with familial hypercholesterolemia (FH) (PMID: 9544745 (1998), 11313767 (2001), 16465405 (2006), 21310417 (2011), 22883975 (2012), 23054246 (2012), 33418990 (2021)), including one compound heterozygous individual (PMID: 22883975 (2012)). It was also reported in individuals with autosomal dominant hypercholesterolemia (PMID: 20145306 (2010), 33740630 (2021)), and coronary artery disease (PMID: 27050191 (2016)). 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 pathogenic.
Comment:
PM2_Supporting+PS4_Moderate+PP4+PM1+PP3_Strong
Comment:
This missense variant (also known as p.Cys88Tyr in the mature protein) replaces cysteine with tyrosine at codon 109 in the LDLR type A repeat 3 of the LDLR protein. This variant alters a conserved cysteine residue that is critical for proper protein folding and function (PMID: 2088165, 6091915, 15952897). Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This LDLR variant has been reported in over 10 heterozygous individuals affected with familial hypercholesterolemia (PMID: 9026534, 11313767, 17094996, 17539906, 20145306, 22883975, 23833242, 24075752, 33418990, 33740630, 34037665). This variant has also been observed in compound heterozygous state with a known pathogenic LDLR variant in an individual affected with severe homozygous familial hypercholesterolemia and extensive atherosclerotic cardiovascular disease, a phenotype expected of having two deleterious LDLR variants (PMID: 22883975, 32276786). Additionally, this variant has been reported in an individual affected with coronary artery disease (PMID: 27050191) and in an individual affected with moderately high total cholesterol despite cholesterol-lowering therapy (PMID: 24956927). This variant has been identified in 1/250250 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
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 |
| The LDLR, APOB, and PCSK9 Variants of Index Patients with Familial Hypercholesterolemia in Russia. | Meshkov A | Genes | 2021 | PMID: 33418990 |
| Design, development and deployment of a web-based patient registry for rare genetic lipid disorders. | Napier KR | Pathology | 2020 | PMID: 32276786 |
| 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 |
| Diagnostic Yield and Clinical Utility of Sequencing Familial Hypercholesterolemia Genes in Patients With Severe Hypercholesterolemia. | Khera AV | Journal of the American College of Cardiology | 2016 | PMID: 27050191 |
| Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. | Do R | Nature | 2015 | PMID: 25487149 |
| Targeted genetic testing for familial hypercholesterolaemia using next generation sequencing: a population-based study. | Norsworthy PJ | BMC medical genetics | 2014 | PMID: 24956927 |
| Detection of variations and identifying genomic breakpoints for large deletions in the LDLR by Ion Torrent semiconductor sequencing. | Faiz F | Atherosclerosis | 2013 | PMID: 24075752 |
| Inheritance pattern of familial hypercholesterolemia and markers of cardiovascular risk. | Kusters DM | Journal of lipid research | 2013 | PMID: 23833242 |
| Use of targeted exome sequencing as a diagnostic tool for Familial Hypercholesterolaemia. | Futema M | Journal of medical genetics | 2012 | PMID: 23054246 |
| Genetic analysis of familial hypercholesterolaemia in Western Australia. | Hooper AJ | Atherosclerosis | 2012 | PMID: 22883975 |
| An APEX-based genotyping microarray for the screening of 168 mutations associated with familial hypercholesterolemia. | Dušková L | Atherosclerosis | 2011 | PMID: 21310417 |
| Molecular characterization of Polish patients with familial hypercholesterolemia: novel and recurrent LDLR mutations. | Chmara M | Journal of applied genetics | 2010 | PMID: 20145306 |
| Update and analysis of the University College London low density lipoprotein receptor familial hypercholesterolemia database. | Leigh SE | Annals of human genetics | 2008 | PMID: 18325082 |
| Multiplex ARMS analysis to detect 13 common mutations in familial hypercholesterolaemia. | Taylor A | Clinical genetics | 2007 | PMID: 17539906 |
| Genetic defects causing familial hypercholesterolaemia: identification of deletions and duplications in the LDL-receptor gene and summary of all mutations found in patients attending the Hammersmith Hospital Lipid Clinic. | Tosi I | Atherosclerosis | 2007 | PMID: 17094996 |
| Six novel mutations of the LDL receptor gene in FH kindred of Sicilian and Paraguayan descent. | Cefalù AB | International journal of molecular medicine | 2006 | PMID: 16465405 |
| Structure and physiologic function of the low-density lipoprotein receptor. | Jeon H | Annual review of biochemistry | 2005 | PMID: 15952897 |
| Mutation detection in patients with familial hypercholesterolaemia using heteroduplex and single strand conformation polymorphism analysis by capillary electrophoresis. | Sozen M | Atherosclerosis. Supplements | 2004 | PMID: 15556093 |
| The UMD-LDLR database: additions to the software and 490 new entries to the database. | Villéger L | Human mutation | 2002 | PMID: 12124988 |
| A "de novo" mutation of the LDL-receptor gene as the cause of familial hypercholesterolemia. | Pisciotta L | Biochimica et biophysica acta | 2002 | PMID: 12009418 |
| A molecular genetic service for diagnosing individuals with familial hypercholesterolaemia (FH) in the United Kingdom. | Heath KE | European journal of human genetics : EJHG | 2001 | PMID: 11313767 |
| Influence of genotype at the low density lipoprotein (LDL) receptor gene locus on the clinical phenotype and response to lipid-lowering drug therapy in heterozygous familial hypercholesterolaemia. The Familial Hypercholesterolaemia Regression Study Group. | Sun XM | Atherosclerosis | 1998 | PMID: 9544745 |
| Characterization of mutations in the low density lipoprotein (LDL)-receptor gene in patients with homozygous familial hypercholesterolemia, and frequency of these mutations in FH patients in the United Kingdom. | Webb JC | Journal of lipid research | 1996 | PMID: 9026534 |
| Three-dimensional structure of a cysteine-rich repeat from the low-density lipoprotein receptor. | Daly NL | Proceedings of the National Academy of Sciences of the United States of America | 1995 | PMID: 7603991 |
| Disulfide bridges of a cysteine-rich repeat of the LDL receptor ligand-binding domain. | Bieri S | Biochemistry | 1995 | PMID: 7548065 |
| Structures and functions of multiligand lipoprotein receptors: macrophage scavenger receptors and LDL receptor-related protein (LRP). | Krieger M | Annual review of biochemistry | 1994 | PMID: 7979249 |
| The LDL receptor locus in familial hypercholesterolemia: mutational analysis of a membrane protein. | Hobbs HH | Annual review of genetics | 1990 | PMID: 2088165 |
| The human LDL receptor: a cysteine-rich protein with multiple Alu sequences in its mRNA. | Yamamoto T | Cell | 1984 | PMID: 6091915 |
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Text-mined citations for rs121908042 ...
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Record last updated Feb 26, 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.