ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.939C>A (p.Cys313Ter)

dbSNP: rs13306512
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237235 SCV000295073 pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge RCV000237235 SCV000322920 pathogenic Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research 0/190 non-FH alleles
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation RCV000237235 SCV000540772 pathogenic Hypercholesterolemia, familial, 1 2016-11-05 criteria provided, single submitter clinical testing
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000237235 SCV000583764 pathogenic Hypercholesterolemia, familial, 1 2017-03-30 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000775228 SCV000909479 pathogenic Familial hypercholesterolemia 2018-03-23 criteria provided, single submitter clinical testing Pathogenic variant based on current evidence: This variant (also known as C292X and FH-Cyprus) changes one nucleotide in exon 6 of the LDLR gene. This creates a premature translational stop signal and is expected to result in an absent or non-functional protein product. Truncating variants in LDLR are known to be pathogenic (PMID: 20809525). While this variant is rare in the general population (0/277264 chromosomes in the Genome Aggregation Database (gnomAD)), it has been reported in multiple individuals affected with familial hypercholesterolemia (PMID: 1301956, 17142622, 21310417, 22698793). Based on available evidence, this variant is classified as Pathogenic.
Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia RCV000237235 SCV001432673 pathogenic Hypercholesterolemia, familial, 1 2019-06-04 criteria provided, single submitter research
Ambry Genetics RCV002446475 SCV002682440 pathogenic Cardiovascular phenotype 2022-08-29 criteria provided, single submitter clinical testing The p.C313* pathogenic mutation (also known as c.939C>A), located in coding exon 6 of the LDLR gene, results from a C to A substitution at nucleotide position 939. This changes the amino acid from a cysteine to a stop codon within coding exon 6. This variant (also referred to as p.C292* and FH Cyprus) has been detected in individuals from numerous familial hypercholesterolemia (FH) cohorts of various ethnic backgrounds, including a homozygous occurrence and co-occurrence with a PCSK9 variant in individuals with features consistent with homozygous FH (Leren TP et al. Atherosclerosis, 2021 04;322:61-66; Hori M et al. Atherosclerosis, 2019 10;289:101-108; Saracoglu E et al. Echocardiography, 2018 09;35:1289-1299; Tichý L et al. Atherosclerosis, 2012 Aug;223:401-8; Noguchi T et al. Atherosclerosis, 2010 May;210:166-72; Glynou K et al. Clin Biochem, 2008 Mar;41:335-42; Humphries SE et al. J Med Genet, 2006 Dec;43:943-9; Xenophontos SL et al. Hum Mutat, 2000 Apr;15:380; Webb JC et al. J Lipid Res, 1996 Feb;37:368-81). Assays performed on patient cells homozygous for this variant indicated significantly reduced LDL-R activity (Webb JC et al. J Lipid Res, 1996 Feb;37:368-81). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Revvity Omics, Revvity RCV000237235 SCV003819498 pathogenic Hypercholesterolemia, familial, 1 2022-03-15 criteria provided, single submitter clinical testing
Invitae RCV000775228 SCV004298339 pathogenic Familial hypercholesterolemia 2023-08-17 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Cys313*) in the LDLR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 251539). This variant is also known as FH Cyprus, Cys292Ter, and C292X. This premature translational stop signal has been observed in individual(s) with familial hypercholesterolemia (PMID: 1301956, 10737984, 30241732, 31491741). This variant is not present in population databases (gnomAD no frequency).
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum RCV000237235 SCV000606275 pathogenic Hypercholesterolemia, familial, 1 no assertion criteria provided research

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