ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.709C>T (p.Arg237Cys)

gnomAD frequency: 0.00001  dbSNP: rs879254657
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel RCV000237333 SCV002506412 uncertain significance Hypercholesterolemia, familial, 1 2022-04-30 reviewed by expert panel curation NM_000527.5(LDLR):c.709C>T (p.Arg237Cys) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence code PM2, PS4_Moderate and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - PopMax MAF = 0.00009799 (0.01%) in South Asian exomes (gnomAD v2.1.1). PS4_Supporting - Variant meets PM2 and is reported in 3 unrelated index cases, two with possible SB criteria (PMID 20236128 and Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation)), one with DLCN >= 6 criteria (PMID 30293936). PP4 - Variant meets PM2 and is reported in 3 unrelated index cases, two with possible SB criteria (PMID 20236128 and Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation)), one with DLCN >= 6 criteria (PMID 30293936).
LDLR-LOVD, British Heart Foundation RCV000237333 SCV000294937 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Labcorp Genetics (formerly Invitae), Labcorp RCV000791408 SCV000821216 pathogenic Familial hypercholesterolemia 2024-08-29 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 237 of the LDLR protein (p.Arg237Cys). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individuals with clinical features of familial hypercholesterolemia (PMID: 20236128, 25463123, 30293936; internal data). ClinVar contains an entry for this variant (Variation ID: 251421). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
MGZ Medical Genetics Center RCV000237333 SCV002579274 uncertain significance Hypercholesterolemia, familial, 1 2021-08-09 criteria provided, single submitter clinical testing

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