ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1731G>T (p.Trp577Cys) (rs875989928)

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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 RCV000237962 SCV000295622 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
GeneDx RCV000254781 SCV000322174 pathogenic not provided 2017-01-10 criteria provided, single submitter clinical testing The W577C variant in the LDLR gene has been previously reported using alternate nomenclature W556C as a heterozygous change in a family affected with familial hypercholesterolemia (Hattori et al., 2002). In this family, the heterozygous presence of the W577C variant was associated with a decrease in both the LDL receptor protein and LDL uptake to 64% of controls (Hattori et al., 2002). The W577C variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The W577C variant is a non-conservative amino acid substitution, which occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants at the same (W577G, W577R, W577S) and nearby residues (Y576C, Y576S, D579A, D579G, D579N, D579Y) have been reported in the Human Gene Mutation Database in association with hypercholesterolemia (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret W577C as a pathogenic variant.
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000237962 SCV000599388 likely pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter curation
Robarts Research Institute,Western University RCV000237962 SCV000782925 uncertain significance Familial hypercholesterolemia 1 2018-01-02 criteria provided, single submitter clinical testing

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