ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.519C>G (p.Cys173Trp) (rs769318035)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000238354 SCV000294767 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Robarts Research Institute,Western University RCV000238354 SCV000484679 likely pathogenic Familial hypercholesterolemia 1 criteria provided, single submitter clinical testing
Invitae RCV000791359 SCV000544646 pathogenic Familial hypercholesterolemia 2018-12-26 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tryptophan at codon 173 of the LDLR protein (p.Cys173Trp). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with familial hypercholesterolemia in single family (PMID: 9452094) and has been observed in three unrelated individuals with familial hypercholesterolemia (PMID: 11462246, 11810272, 25962062). This variant is also known as p.Cys152Trp in the literature. A different missense substitution at this codon (p.Cys173Gly) has been determined to be pathogenic (PMID: 7489239, 20019594). This variant is also known as p.Cys152Gly in the literature. This suggests that the cystine residue is critical for LDLR protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000478384 SCV000568521 pathogenic not provided 2017-03-28 criteria provided, single submitter clinical testing The C173W pathogenic variant in the LDLR gene, also denoted as C152W due to the use of alternate nomenclature, has been previously reported in association with familial hypercholesterolemia in several individuals from various ethnic backgrounds (Couture et al., 1998; Morash et al., 1998; Ebhardt et al., 1999; Fouchier et al., 2001; Shin et al., 2015). This variant has been shown to segregate with disease in multiple affected relatives from two unrelated families (Couture et al., 1998; Morash et al., 1998). This variant is not observed large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The C173W variant is a non-conservative amino acid substitution which affects an essential cysteine residue that is conserved across species. Moreover, functional studies indicate that the C173W variant results in abnormal ligand binding and receptor internalization (Plewa et al., 2006). Furthermore, missense variants at the same residue (C173G, C173Y) have also been reported in association with FH (Stenson et al., 2014).
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000238354 SCV000583691 pathogenic Familial hypercholesterolemia 1 2017-03-30 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000478384 SCV000987443 pathogenic not provided criteria provided, single submitter clinical testing
Brunham Lab, Centre for Heart and Lung Innovation,University of British Columbia RCV000238354 SCV001432610 pathogenic Familial hypercholesterolemia 1 2019-05-11 criteria provided, single submitter research
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000238354 SCV000606146 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000478384 SCV000924845 likely pathogenic not provided 2015-07-24 no assertion criteria provided provider interpretation The patient had genetic testing for the familial hypercholesterolemia panel. The test included sequencing of three genes associated with familial hypercholesterolemia: LDLR, APOB and PCSK9. Results showed that the following variant was identified: - p.C173W (c.519C>G) in the LDLR gene. The lab classifies this as a pathogenic mutation. Given sufficient case data and it's disruption of the binding site of the low density lipoprotein receptor protein we consider this variant likely pathogenic and we feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in at least five unrelated cases of familial hypercholesterolemia (not including this patient's family). There is two generation segregation data presented in one family with four affected individuals. Couture, et al., 1998 reported a novel variant p.C173W (reported as p.C152W and c.519C>G in the paper). The C-to-G transversion at nucleotide 519 results in a change in the highly conserved cysteine at the C-terminal end in the fourth of the seven tandem cysteine repeats that for the binding site for LDLR (Bieri et al., 1995; Mehta et al., 1991). They variant segregated with FH in four individuals who had LDLs of 178, 298, 200 and 263, three of whom had tendinous xanthomas and two of which had coronary artery disease. Ebhardt, et al., 1999 reported a patient with p.C173W (reported as p.C152W and c.519C>G in the paper) in a Northern German individual that segregated with FH in the family (no details on number of individuals). Fouchier, et al., 2001; Morash, et al., 1998; Nauck, et al., 1997 all reported a patient with p.C173W (reported as p.C152W). The do not offer clinical details other than each patient had a diagnosis of familial hypercholesterolemia. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging (HumVar: 1.00) and Mutation Taster predicts that it's disease causing (0.999). The cysteine at codon 173 is conserved across species, as are neighboring amino acids. Other variants have been reported in association with disease at this codon (C152R in a greek patient with compound heterozygous FH) and nearby codons (167, 175, and 177 in clinvar). In total the variant has not been seen in 100 published controls and individuals from publicly available population datasets. There is no missense variation at codon 173 listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of July 24, 2015). There were 16,512 individuals of South Asian descent.

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