Submissions for variant NM_000527.5(LDLR):c.986G>A (p.Cys329Tyr) (rs761954844)

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000211666	SCV000295127	likely pathogenic	Familial hypercholesterolemia 1	2016-03-25	criteria provided, single submitter	literature only
Robarts Research Institute,Western University	RCV000211666	SCV000484751	likely pathogenic	Familial hypercholesterolemia 1		criteria provided, single submitter	clinical testing
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	RCV000211666	SCV000503275	likely benign	Familial hypercholesterolemia 1	2016-12-16	criteria provided, single submitter	clinical testing	subject mutated among 2600 FH index cases screened = 1 / previously described in association with FH (linked to ethnicity ?) / Software predictions: Damaging
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation	RCV000211666	SCV000540780	likely pathogenic	Familial hypercholesterolemia 1	2016-11-05	criteria provided, single submitter	clinical testing	Disrupt disulfide bridge between Cys318 and Cys329.
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000211666	SCV000599354	pathogenic	Familial hypercholesterolemia 1	2016-03-01	criteria provided, single submitter	curation
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000211666	SCV000268597	pathogenic	Familial hypercholesterolemia 1	2008-11-17	no assertion criteria provided	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum	RCV000211666	SCV000606290	pathogenic	Familial hypercholesterolemia 1		no assertion criteria provided	research
Broad Institute Rare Disease Group,Broad Institute	RCV000211666	SCV001423089	likely pathogenic	Familial hypercholesterolemia 1	2020-01-22	no assertion criteria provided	curation	The p.Cys329Tyr variant in LDLR has been reported in at least 25 individuals (including 17 Taiwanese, 2 Russian, 2 Chinese, 1 Filipino, and 1 Czech individuals) with Familial Hypercholesterolemia (PMID: 22353362, 9763532, 11810272, 15701167, 16205024, 27765764, 22698793), and has been identified in 0.01003% (2/19938) of East Asian chromosomes and 0.005645% (2/35428) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs761954844). 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 as a likely benign variant, likely pathogenic variant, and pathogenic variant in ClinVar (Variation ID: 226344). In vitro functional studies with transfected COS cells provide some evidence that the p.Cys329Tyr variant may impact LDL receptor activity (PMID: 26608663). However, these types of assays may not accurately represent biological function. 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 variant with a different amino acid change at the same position (p.Cys329Phe) has been reported in association with disease in ClinVar, supporting that a change at this position may not be tolerated (Variation ID: 251586). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS4, PS3_supporting, PM5_supporting, PP3 (Richards 2015).