ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.2029T>C (p.Cys677Arg)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000527.5(LDLR):c.2029T>C (p.Cys677Arg)
Variation ID: 226384 Accession: VCV000226384.15
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 19p13.2 19: 11120411 (GRCh38) [ NCBI UCSC ] 19: 11231087 (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 May 1, 2024 Dec 13, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000527.5:c.2029T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000518.1:p.Cys677Arg missense NM_001195798.2:c.2029T>C NP_001182727.1:p.Cys677Arg missense NM_001195799.2:c.1906T>C NP_001182728.1:p.Cys636Arg missense NM_001195800.2:c.1525T>C NP_001182729.1:p.Cys509Arg missense NM_001195803.2:c.1606+178T>C intron variant NC_000019.10:g.11120411T>C NC_000019.9:g.11231087T>C NG_009060.1:g.36031T>C LRG_274:g.36031T>C LRG_274t1:c.2029T>C LRG_274p1:p.Cys677Arg P01130:p.Cys677Arg - Protein change
- C677R, C636R, C509R
- Other names
- FH New York-3
- NP_000518.1:p.C677R
- Canonical SPDI
- NC_000019.10:11120410:T:C
-
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
Trans-Omics for Precision Medicine (TOPMed) 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
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 |
4059 | 4334 |
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 (4) |
criteria provided, multiple submitters, no conflicts
|
Apr 13, 2018 | RCV000211671.11 | |
Pathogenic (1) |
criteria provided, single submitter
|
Dec 13, 2023 | RCV000791370.6 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Feb 18, 2022 | RCV001843494.3 | |
Pathogenic (1) |
criteria provided, single submitter
|
Dec 15, 2021 | RCV002415889.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
Oct 11, 2019 | RCV004017508.1 |
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. |
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: SCV000295824.2
First in ClinVar: Jul 29, 2016 Last updated: Oct 13, 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
|
|
Likely pathogenic
(-)
|
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: SCV000484752.1
First in ClinVar: Dec 17, 2016 Last updated: Dec 17, 2016 |
Number of individuals with the variant: 1
|
|
Likely pathogenic
(Apr 13, 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: SCV000839986.1
First in ClinVar: Oct 13, 2018 Last updated: Oct 13, 2018 |
Comment:
This c.2029T>C (p.Cys677Arg) variant in the LDLR gene has been reported in multiple individuals with familial hypercholesterolemia (PMID: 1301956, 10208479, 10559517) or myocardial infarction (PMID … (more)
This c.2029T>C (p.Cys677Arg) variant in the LDLR gene has been reported in multiple individuals with familial hypercholesterolemia (PMID: 1301956, 10208479, 10559517) or myocardial infarction (PMID 25487149). Functional studies have indicated that the p.Cys677Arg variant in the LDLR protein has 5-15% receptor activity compared to wild-type LDLR protein (PMID: 1301956). The c.2029T>C variant is rare in the general population and cysteine at position 677 of the LDLR protein is highly evolutionarily conserved. The c.2029T>C (p.Cys677Arg) variant in the LDLR gene is classified as likely pathogenic. (less)
|
|
Pathogenic
(Dec 13, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000830362.5
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 677 of the LDLR protein … (more)
This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 677 of the LDLR protein (p.Cys677Arg). This variant is present in population databases (rs775092314, gnomAD 0.0009%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 1301956, 10208479, 17142622, 19487412, 22883975, 27680772, 27765764). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Cys656Arg. ClinVar contains an entry for this variant (Variation ID: 226384). 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.Cys677 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 9763532, 16389549, 28235710), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Likely pathogenic
(Aug 17, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: yes
Allele origin:
germline
|
AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002502712.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Secondary finding: no
|
|
Pathogenic
(Feb 18, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002102633.2
First in ClinVar: Mar 12, 2022 Last updated: Mar 04, 2023 |
Comment:
Also known as FH New York-1 and p.C656R; Located within the LDL-receptor EGF precursor domain 3, and participates in disulfide bonding with another cysteine residue … (more)
Also known as FH New York-1 and p.C656R; Located within the LDL-receptor EGF precursor domain 3, and participates in disulfide bonding with another cysteine residue which is critical for correct protein structure (Sudhof et al., 1985; Rudenko et al., 2002); 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; This variant is associated with the following publications: (PMID: 10559517, 25487149, 1301956, 16389549, 17142622, 22883975, 27680772, 27765764, 31447099, 32041611, 34037665, 33087929, 2988123, 12459547, 10208479, 19487412) (less)
|
|
Likely Pathogenic
(Oct 11, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Homozygous familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004847793.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Cys677Arg variant in LDLR has been reported in at least 7 individuals with hypercholesterolemia and segregated with disease in 6 affected individuals from 1 … (more)
The p.Cys677Arg variant in LDLR has been reported in at least 7 individuals with hypercholesterolemia and segregated with disease in 6 affected individuals from 1 family (Hobbs 1992, Heath 1999, Humphries 2006, Bima 2009, Hooper 2012, Martin 2016, Wang 2016). It has also been identified in 1/113610 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and has been reported in ClinVar (Variation ID 226384). An in vitro functional study and computational prediction tools support an impact on protein function (Hobbs 1992). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant familial . ACMG/AMP Criteria applied: PM2, PS4_Moderate, PP1_Moderate, PP3, PS3_Supporting. (less)
|
|
Pathogenic
(Dec 15, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002718691.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.C677R pathogenic mutation (also known as c.2029T>C), located in coding exon 14 of the LDLR gene, results from a T to C substitution at … (more)
The p.C677R pathogenic mutation (also known as c.2029T>C), located in coding exon 14 of the LDLR gene, results from a T to C substitution at nucleotide position 2029. The cysteine at codon 677 is replaced by arginine, an amino acid with highly dissimilar properties. This alteration was detected in conjunction with another alteration in the LDLR gene in an individual whose protein activity was 5-15% of normal (Hobbs HH et al. Hum Mutat. 1992;1(6):445-66). Subsequent studies observed this alteration in several individuals diagnosed with familial hypercholesterolemia (FH) (Humphries SE et al. J Mol Med. 2006; 84(3):203-14; Tosi I et al. Atherosclerosis. 2007;194(1):102-11). In a case report, this alteration was described to co-segregate with FH in multiple individuals in one family (Bima AI et al. Ann Clin Biochem. 2009;46(Pt 5):420-2). Another alteration affecting the same codon (p.C677Y c.2030G>A) has also been described in patients with FH (Salazar LA et al. Hum Mutat. 2002;19(4):462-3). Based on the supporting evidence, p.C677R is interpreted as a disease-causing mutation. (less)
|
|
Pathogenic
(Jun 05, 2008)
|
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: SCV000268653.1
First in ClinVar: May 22, 2016 Last updated: May 22, 2016 |
Number of individuals with the variant: 4
|
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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
Limited-Variant Screening vs Comprehensive Genetic Testing for Familial Hypercholesterolemia Diagnosis. | Sturm AC | JAMA cardiology | 2021 | PMID: 34037665 |
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 |
The genetic spectrum of familial hypercholesterolemia in the central south region of China. | Xiang R | Atherosclerosis | 2017 | PMID: 28235710 |
Polygenic Versus Monogenic Causes of Hypercholesterolemia Ascertained Clinically. | Wang J | Arteriosclerosis, thrombosis, and vascular biology | 2016 | PMID: 27765764 |
Genetic diagnosis of familial hypercholesterolaemia using a rapid biochip array assay for 40 common LDLR, APOB and PCSK9 mutations. | Martin R | Atherosclerosis | 2016 | PMID: 27680772 |
Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. | Do R | Nature | 2015 | PMID: 25487149 |
Genetic analysis of familial hypercholesterolaemia in Western Australia. | Hooper AJ | Atherosclerosis | 2012 | PMID: 22883975 |
Hypobetalipoproteinaemia secondary to chronic hepatitis C virus infection in a patient with familial hypercholesterolaemia. | Bima AI | Annals of clinical biochemistry | 2009 | PMID: 19487412 |
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 |
Genetic causes of familial hypercholesterolaemia in patients in the UK: relation to plasma lipid levels and coronary heart disease risk. | Humphries SE | Journal of medical genetics | 2006 | PMID: 17142622 |
Mutational analysis in UK patients with a clinical diagnosis of familial hypercholesterolaemia: relationship with plasma lipid traits, heart disease risk and utility in relative tracing. | Humphries SE | Journal of molecular medicine (Berlin, Germany) | 2006 | PMID: 16389549 |
Mutation screening and genotype:phenotype correlation in familial hypercholesterolaemia. | Graham CA | Atherosclerosis | 1999 | PMID: 10559517 |
The type of mutation in the low density lipoprotein receptor gene influences the cholesterol-lowering response of the HMG-CoA reductase inhibitor simvastatin in patients with heterozygous familial hypercholesterolaemia. | Heath KE | Atherosclerosis | 1999 | PMID: 10208479 |
Mutations in the low-density lipoprotein receptor gene in Chinese familial hypercholesterolemia patients. | Mak YT | Arteriosclerosis, thrombosis, and vascular biology | 1998 | PMID: 9763532 |
Molecular genetics of the LDL receptor gene in familial hypercholesterolemia. | Hobbs HH | Human mutation | 1992 | PMID: 1301956 |
click to load more click to collapse |
Text-mined citations for rs775092314 ...
HelpRecord last updated Sep 01, 2024
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.