Submissions for variant NM_000527.5(LDLR):c.1118G>A (p.Gly373Asp)

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000237895	SCV000295229	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	RCV000237895	SCV000503300	likely pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subjects mutated among 2600 FH index cases screened = 3 / FH-Potenza-2 / Software predictions: Damaging
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000237895	SCV000583791	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000237895	SCV000588555	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Fundacion Hipercolesterolemia Familiar	RCV000237895	SCV000607560	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Iberoamerican FH Network	RCV000237895	SCV000748096	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000791447	SCV000825010	pathogenic	Familial hypercholesterolemia	2023-11-08	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 373 of the LDLR protein (p.Gly373Asp). This variant is present in population databases (no rsID available, gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 9974426, 11810272, 11933210, 15241806, 21382890, 23375686, 25461735). This variant is also known as p.Gly352Asp. ClinVar contains an entry for this variant (Variation ID: 251673). 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 with a positive predictive value of 95%. This variant disrupts the p.Gly373 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 16159606, 20145306), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	RCV000237895	SCV001653621	likely pathogenic	Hypercholesterolemia, familial, 1	2021-05-24	criteria provided, single submitter	clinical testing
GeneDx	RCV002243924	SCV002513575	likely pathogenic	not provided	2024-05-13	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as p.(G352D) and FH Potenza-2; This variant is associated with the following publications: (PMID: 33258288, 30270055, 11810272, 11933210, 21382890, 30586733, WerutskyCA2023[Article], 37739193, 36464169, 9974426, 24529145, 15241806, 28958694, 33508743, 10978268, 25461735, 32977124, 23375686, 34037665, 35177841, 35339733, 34297352)
Ambry Genetics	RCV002436075	SCV002752727	pathogenic	Cardiovascular phenotype	2021-11-17	criteria provided, single submitter	clinical testing	The p.G373D pathogenic mutation (also known as c.1118G>A), located in coding exon 8 of the LDLR gene, results from a G to A substitution at nucleotide position 1118. The glycine at codon 373 is replaced by aspartic acid, an amino acid with similar properties. This alteration has been detected in both the homozygous and heterozygous states in multiple individuals meeting diagnostic criteria for familial hypercholesterolemia (FH) (Bertolini S et al. Arterioscler. Thromb. Vasc. Biol., 1999 Feb;19:408-18; Mozas P et al. Hum. Mutat., 2004 Aug;24:187; Noto D et al. Pediatr. Res., 2010 Feb;67:200-4; Dušková L et al. Atherosclerosis, 2011 May;216:139-45; Jannes CE et al. Atherosclerosis, 2015 Jan;238:101-7; Scicali R et al. Nutr Metab Cardiovasc Dis, 2018 01;28:35-43; Corral P et al. Atherosclerosis, 2018 10;277:256-261; Khera AV et al. Circulation, 2019 Mar;139:1593-1602; Di Taranto MD et al. Clin Genet, 2021 11;100:529-541). In addition, this alteration 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 supporting evidence, this alteration is interpreted as a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000791447	SCV004813643	pathogenic	Familial hypercholesterolemia	2024-02-27	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.1118G>A (p.Gly373Asp), also referred to as p.Gly352Asp, results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.1e-06 in 1613724 control chromosomes (gnomAD). c.1118G>A has been reported in the literature in at least two homozygous individuals and multiple heterozygous individuals affected with Familial Hypercholesterolemia (e.g. Bertolini_1999, Bertolini_2000, Fouchier_2001, Mozas_2004, Di Taranto_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 9974426, 10978268, 34297352, 11810272, 15241806). ClinVar contains an entry for this variant (Variation ID: 251673). Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000237895	SCV004848515	likely pathogenic	Hypercholesterolemia, familial, 1	2021-06-29	criteria provided, single submitter	clinical testing	The p.Gly373Asp variant in LDLR, also described as p.Gly352Asp in the literature, has been previously reported in >15 individuals with hypercholesterolemia, including 1 individual with familial hypercholesterolemia (FH) and tendon xanthoma who was homozygous for the variant, and segregated in at least 1 affected family member (Bertolini 1999 PMID: 9974426, Fouchier 2001 PMID: 11810272, Salazar 2002 PMID: 11933210, Mozas 2004 PMID: 15241806, van der Graaf 2011 PMID: 21382890, Bertolini 2013 PMID: 23375686, Jannes 2015 PMID: 25461735, Scicali 2017 PMID: 28958694, Corral 2018 PMID: 30270055). It has also been reported in 1 individual with early onset myocardial infarction (Khera 2019 PMID: 30586733). This variant has been reported by other clinical laboratories in ClinVar (Variation ID: 251673) and has been identified in 0.0004% (1/282736) of pan-ethnic chromosomes by gnomAD (https://gnomad.broadinstitute.org/). Computational prediction tools and conservation analysis support an impact to the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant FH. ACMG/AMP Criteria applied: PS4, PM2_Supporting, PP3, PM3_supporting.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000237895	SCV000606332	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Natera, Inc.	RCV000791447	SCV001460269	pathogenic	Familial hypercholesterolemia	2020-09-16	no assertion criteria provided	clinical testing