Submissions for variant NM_000527.5(LDLR):c.1045C>T (p.Gln349Ter) (rs748300548)

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000237544	SCV000295157	pathogenic	Familial hypercholesterolemia 1	2016-03-25	criteria provided, single submitter	literature only
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	RCV000237544	SCV000503285	pathogenic	Familial hypercholesterolemia 1	2016-12-16	criteria provided, single submitter	clinical testing	subject mutated among 2600 FH index cases screened = 1 , family member = 1 with co-segregation
Fundacion Hipercolesterolemia Familiar	RCV000237544	SCV000607547	uncertain significance	Familial hypercholesterolemia 1	2016-03-01	criteria provided, single submitter	research
Robarts Research Institute,Western University	RCV000237544	SCV000782905	pathogenic	Familial hypercholesterolemia 1	2018-01-02	criteria provided, single submitter	clinical testing
Broad Institute Rare Disease Group,Broad Institute	RCV000237544	SCV001422911	pathogenic	Familial hypercholesterolemia 1	2020-01-22	no assertion criteria provided	curation	The p.Gln349Ter (sometimes called p.Gln328Ter) variant in LDLR has been reported in 3 individuals (including 1 Spanish individual) with Familial Hypercholesterolemia, segregated with disease in 2 affected relatives from 1 family in the literature and ClinVar (PMID: 11668640; Variation ID: 251611), and has been identified in 0.006064% (1/16490) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs748300548). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a dominant frequency for a disease with clinical variability/reduced penetrance. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. The number of reported affected individuals with this variant is slightly greater than expected compared to non-affected individuals with this variant. This variant has also been reported as a VUS and a pathogenic variant in ClinVar (Variation ID: 251611). This nonsense variant leads to a premature termination codon at position 349, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the LDLR gene is an established disease mechanism in Familial Hypercholesterolemia. In summary, this variant meets criteria to be classified as pathogenic for Familial Hypercholesterolemia in an autosomal dominant manner based on the predicted impact of the variant and multiple occurrences in individuals with Familial Hypercholesterolemia. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PS4_Supporting (Richards 2015).