ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.325T>C (p.Cys109Arg) (rs140807148)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237408 SCV000294630 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000237408 SCV000322893 likely pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research 0/190 non-FH alleles; 0/77 healthy control individuals
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation RCV000237408 SCV000540726 likely pathogenic Familial hypercholesterolemia 1 2016-11-05 criteria provided, single submitter clinical testing Disrupt disulfide bridge between Cys109 and Cys121.
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000237408 SCV000583661 pathogenic Familial hypercholesterolemia 1 2017-03-30 criteria provided, single submitter clinical testing
Department of Human Genetics,Laborarztpraxis Dres. Walther, Weindel und Kollegen RCV000237408 SCV000987037 pathogenic Familial hypercholesterolemia 1 2018-05-11 criteria provided, single submitter clinical testing The mutation occurs at protein level at position 109 (position 88 of the mature protein) to exchange the amino acid cysteine for arginine. This change has already been described in the literature as FH Munster-1 allele, detected in patients with familial hypercholesterolemia, and associated with elevated cholesterol and LDL-C levels. It leads to a strong reduction of LDL receptor activity. PMID: 11313767, 1301956
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000237408 SCV000606086 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research
Broad Institute Rare Disease Group, Broad Institute RCV000237408 SCV001422629 uncertain significance Familial hypercholesterolemia 1 2020-01-22 no assertion criteria provided curation The p.Cys109Arg variant in LDLR has been reported in at least 7 individuals (including 2 Czech, 2 Portuguese, 1 Dutch, 1 German, and 1 Mexican individuals) with Familial Hypercholesterolemia, segregated with disease in 3 affected relatives from 1 family (PMID: 16250003, 1301956, 16314194, 22698793, 24627126), and has been identified in 0.001771% (2/112906) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD,; dbSNP rs140807148). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported pathogenic and likely pathogenic in ClinVar (Variation ID: 251156). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional missense variant (p.Cys109Ser) is likely pathogenic with a different amino acid change at the same position and has been reported in association with disease in ClinVar, supporting that a change at this position may not be tolerated (PMID: 12009418; Variation ID: 3743). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM5_Supporting, PS4_Moderate, PP3, PP1 (Richards 2015).

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