ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1860G>T (p.Trp620Cys) (rs875989933)

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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 RCV000211660 SCV000295723 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Color Health, Inc RCV001188071 SCV001355018 uncertain significance Familial hypercholesterolemia 2020-07-23 criteria provided, single submitter clinical testing This variant (also known as p.Trp599Cys in the mature protein) is a missense variant that changes a highly conserved Trp (W) in the sixth LDLR type B (YWTD) repeat of the EGF precursor homology domain of the LDLR protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant but a different variant at the same position, p.Trp620Arg, has been suggested to reduce LDLR stability and have deleterious impact on protein function (PMID: 9409298). This variant has been reported in definite and possible familial hypercholesterolemia subjects in UK (PMID: 17539906, 11313767). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may play a pathogenic role, additional functional and clinical studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as Variant of Uncertain Significance.
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000211660 SCV000268643 pathogenic Familial hypercholesterolemia 1 2013-02-06 no assertion criteria provided clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV001188071 SCV001423039 uncertain significance Familial hypercholesterolemia 2020-01-22 no assertion criteria provided curation The p.Trp620Cys variant in LDLR has been reported in 1 individual from the UK with familial hypercholesterolemia (PMID: 17539906), and was absent from large population studies. This variant has also been reported in ClinVar as likely pathogenic (Variation ID: 226376). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3 (Richards 2015).

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