Submissions for variant NM_000527.5(LDLR):c.1694G>C (p.Gly565Ala)

dbSNP: rs28942082

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000211673	SCV000295583	likely pathogenic	Hypercholesterolemia, familial, 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	RCV000211673	SCV000503386	likely pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subjects mutated among 2600 FH index cases screened = 2 , family member = 1 with co-segregation / Other mutations at same codon/software prediction damaging
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000211673	SCV000583864	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002408916	SCV002715416	likely pathogenic	Cardiovascular phenotype	2022-05-26	criteria provided, single submitter	clinical testing	The p.G565A variant (also known as c.1694G>C), located in coding exon 11 of the LDLR gene, results from a G to C substitution at nucleotide position 1694. The glycine at codon 565 is replaced by alanine, an amino acid with similar properties. This alteration has been reported in several individuals with familial hypercholesterolemia (FH) (Heath KE et al. Eur J Hum Genet, 2001 Apr;9:244-52; Laurie AD et al. Atheroscler Suppl, 2004 Dec;5:13-5; Taylor A et al. Clin Genet, 2007 Jun;71:561-8). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003581586	SCV004298370	pathogenic	Familial hypercholesterolemia	2023-04-25	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 565 of the LDLR protein (p.Gly565Ala). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly565 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 2901412, 12436241, 16740646, 23375686). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function. ClinVar contains an entry for this variant (Variation ID: 226366). This variant is also known as G544A. This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 11313767, 15556094). This variant is not present in population databases (gnomAD no frequency).
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000211673	SCV000268629	pathogenic	Hypercholesterolemia, familial, 1	2013-05-28	no assertion criteria provided	clinical testing