ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.463T>C (p.Cys155Arg)

dbSNP: rs879254535
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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 RCV000237283 SCV000294725 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia RCV000237283 SCV001432651 pathogenic Hypercholesterolemia, familial, 1 2019-06-05 criteria provided, single submitter research
Ambry Genetics RCV002338778 SCV002635279 likely pathogenic Cardiovascular phenotype 2019-01-17 criteria provided, single submitter clinical testing The p.C155R variant (also known as c.463T>C), located in coding exon 4 of the LDLR gene, results from a T to C substitution at nucleotide position 463. The cysteine at codon 155, located at LDLR class A repeat 4, is replaced by arginine, an amino acid with highly dissimilar properties. Pathogenic LDLR mutations that result in the substitution or generation of cysteine residues within the cysteine-rich LDLR class A repeats and EGF-like domains are common in familial hypercholesterolemia (FH) (Villéger L. Hum Mutat. 2002;20(2):81-7). This variant was reported in an FH cohort with limited clinical details provided (Yu W et al. Atherosclerosis, 2002 Dec;165:335-42). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of LDLR class A repeat 4 (Ambry internal data). Alternate amino acid substitutions at this position, including p.C155G (legacy p.C134G) and p.C155F, have been reported in individuals with FH (Hobbs HH et al. Hum. Mutat., 1992;1:445-66; Lombardi MP et al. Clin. Genet., 2000 Feb;57:116-24; van der Graaf A et al. Circulation, 2011 Mar;123:1167-73). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum RCV000237283 SCV000606126 pathogenic Hypercholesterolemia, familial, 1 no assertion criteria provided research

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