ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.828C>G (p.Cys276Trp)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237617 SCV000295005 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000237617 SCV000503242 pathogenic Hypercholesterolemia, familial, 1 2016-12-16 criteria provided, single submitter clinical testing subject mutated among 2600 FH index cases screened = 1 , family members = 5 with co-segregation / previously described in association with FH / Software predictions: Conflicting
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000237617 SCV000588521 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research
All of Us Research Program, National Institutes of Health RCV000237617 SCV004836951 likely pathogenic Hypercholesterolemia, familial, 1 2023-10-02 criteria provided, single submitter clinical testing This missense variant replaces cysteine with tryptophan at codon 276 in the LDLR type A repeat 7 of the LDLR protein. This variant is also known as p.Cys255Trp in the mature protein and as FH Sassari-3 in the literature. 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 variant has been reported in at least 10 individuals affected with familial hypercholesterolemia (PMID: 10634824, 10978268, 19026292, 23375686, 24529145, 25461735, 28161202, 30293936) and was shown to segregate with disease in one family (PMID: 28161202). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Multiple different variants affecting the same codon, p.Cys276Gly, p.Cys276Arg, p.Cys276Tyr, and p.Cys276Ser, are considered to be disease-causing (ClinVar variation ID: 251480, 251479, 251481, 183096), indicating that cysteine at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Likely Pathogenic.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum RCV000237617 SCV000606241 pathogenic Hypercholesterolemia, familial, 1 no assertion criteria provided research

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