ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.517T>C (p.Cys173Arg) (rs879254558)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237161 SCV000294762 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Robarts Research Institute,Western University RCV000237161 SCV000484745 likely pathogenic Familial hypercholesterolemia 1 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000587092 SCV000697235 pathogenic Familial hypercholesterolemia 2017-04-24 criteria provided, single submitter clinical testing Variant summary: The LDLR c.517T>C (p.Cys173Arg) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant and LDL receptor activity in fibroblast from compound heterozygote with p.S265R (known DV) was shown to be 5-15% of wt (Hobbs, 1998). Most of the published reports cite the variant as partially defective allele although now functional studies confirming deleterious impact on the protein function solely by the variant of interest have been published at the time of evaluation. The variant is absent from the large control population datasets of ExAC or gnomAD, but has been reported in multiple affected individuals with biochemically and clinically confirmed FH in heterozygous state (Miltiadous, 2001; Mollaki, 2014) and severe FH in compound heterozygosity with a known pathogenic alleles (Hobbs, 1998; Su, 2009). The c.517T>C is considered to be one of the Greek founder mutations. In addition, a clinical diagnostic laboratory/reputable database classified this variant as Pathogenic. Taken together, this variant is classified as Pathogenic.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000237161 SCV000606143 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research

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