ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.938G>A (p.Cys313Tyr)

gnomAD frequency: 0.00001  dbSNP: rs875989911
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000211642 SCV000295072 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Fundacion Hipercolesterolemia Familiar RCV000211642 SCV000607528 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research
Invitae RCV002229197 SCV000752418 pathogenic Familial hypercholesterolemia 2021-08-02 criteria provided, single submitter clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000211642 SCV000840001 likely pathogenic Hypercholesterolemia, familial, 1 2018-04-25 criteria provided, single submitter clinical testing This c.938G>A (p.Cys313Tyr) variant in the LDLR gene has been reported in multiple familial hypercholesterolemia patients [PMID: 9259195, 11857755, 11810272] but not observed in general population according to gnomad database. This variant has been reported by multiple clinical test center as disease-causing according to ClinVar database. Multiple in silico predictions suggest this cysteine to tyrosine is deleterious. Multiple variants causing cysteine at amino acid position 313 change to other amino acids have been reported as disease-causing in literature [PMID: 19318025, 15823288, 11257257]. Based upon above evidences, c.938G>A (p.Cys313Tyr) variant in the LDLR gene is classified as likely pathogenic.
Laboratory for Molecular Medicine,Mass General Brigham Personalized Medicine RCV000826175 SCV000967714 likely pathogenic Homozygous familial hypercholesterolemia 2019-03-03 criteria provided, single submitter clinical testing The p.Cys313Tyr variant in LDLR (also described as p.Cys292Tyr in the literature) has been reported in >10 individuals with familial hypercholesterolemia (FH), of which 2 are in the compound heterozygous state (Day 1997, Thiart 2000, Fouchier 2001, Bunn 2002, Van der Graaf 2011, Martin 2016). It has also been reported in ClinVar (Variation ID: 226339) and was absent from large population studies. Computational prediction tools and conservation analysis suggest that the p.Cys131Tyr variant may impact the protein. This variant is located in the last three bases of the exon, which is part of the 5’ splice region. Computational tools do not suggest an impact to splicing. Additionally, other missense variants at this amino acid position (p.Cys313Arg, p.Cys313Gly and p.Cys313Trp) have been reported in individuals with familial hypercholesterolemia (Human Gene Mutation Database: Stenson 2017), suggesting that changes at this position may not be tolerated. In summary, although additional studies are required to fully establish its clinical significance, the p.Cys313Tyr variant is likely pathogenic. The ACMG/AMP Criteria applied (Richards 2015): PS4_Moderate, PM2, PP3, PM5_Supporting.
AiLife Diagnostics, AiLife Diagnostics RCV002223822 SCV002502951 likely pathogenic not provided 2020-05-08 criteria provided, single submitter clinical testing
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000211642 SCV000268591 pathogenic Hypercholesterolemia, familial, 1 2010-03-18 no assertion criteria provided clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000211642 SCV000606274 pathogenic Hypercholesterolemia, familial, 1 no assertion criteria provided research

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