Submissions for variant NM_000527.5(LDLR):c.758G>C (p.Arg253Pro)

dbSNP: rs139507589

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000238279	SCV002506380	uncertain significance	Hypercholesterolemia, familial, 1	2022-04-22	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.758G>C (p.Arg253Pro) variant is classified as Uncertain significance – insufficient evidence for Familial Hypercholesterolemia by applying evidence PM2, PP3, and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (v2.1.1). PP3 - REVEL = 0.77, which is above the threshold of 0.75. PP4 - Variant meets PM2 and was identified in 1 index case with Simon Broome criteria for FH (PMID: 20236128) after alternative causes of cholesterol were excluded. Note: two other missense variants at this same codon have been reported: 1) NM_000527.5(LDLR):c.757C>T (p.Arg253Trp); 2) NM_000527.5(LDLR):c.758G>A (p.Arg253Gln); however, both are VUS by these LDLR guidelines (PM5 not applicable).
LDLR-LOVD, British Heart Foundation	RCV000238279	SCV000294953	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only