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

dbSNP: rs875989933

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000211660	SCV000295723	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Color Diagnostics, LLC DBA Color Health	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.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001188071	SCV001423039	uncertain significance	Familial hypercholesterolemia	2020-01-22	criteria provided, single submitter	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).
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000211660	SCV000268643	pathogenic	Hypercholesterolemia, familial, 1	2013-02-06	no assertion criteria provided	clinical testing