Submissions for variant NM_000527.5(LDLR):c.912C>G (p.Asp304Glu)

dbSNP: rs875989909

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000211616	SCV002506361	likely pathogenic	Hypercholesterolemia, familial, 1	2022-04-05	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.912C>G (p.Asp304Glu) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PP3, PM5, PS4_supporting, 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 (gnomAD v2.1.1), so PM2 is Met. PP3 - REVEL = 0.871. It is above 0.75, so PP3 is Met. PM5 - 4 other missense variants in the same codon: - NNM_000527.5(LDLR):c.910G>A (p.Asp304Asn) (ClinVar ID 3692) - Pathogenic by these guidelines - NM_000527.5(LDLR):c.910G>C (p.Asp304His) (ClinVar ID 440612) - VUS by these guidelines - NM_000527.5(LDLR):c.911A>T (p.Asp304Val) (ClinVar ID 440613) - VUS by these guidelines - NM_000527.5(LDLR):c.910G>T (p.Asp304Tyr) (ClinVar ID 251517) - Likely pathogenic by these guidelines There is 1 variant in the same codon classified as Pathogenic by these guidelines, so PM5 is Met. PS4_supporting - Variant meets PM2 and is identified in at least 2 unrelated index cases: 1 index case who fulfils DLCN>6 criteria for FH from Robarts Research Institute and 1 index case who fulfils Simon Broome criteria for FH from MRC Clinical Sciences Centre, London UK (Tosi et al, 2007)(PMID: 17094996), so PS4_Supporting is Met. PP4 - Variant meets PM2 and is identified in at least 2 unrelated index cases as described in PS4, PP4 is Met.
LDLR-LOVD, British Heart Foundation	RCV000211616	SCV000295047	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	RCV000211616	SCV000503251	likely pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subject mutated among 2600 FH index cases screened = 1 / FH-Baltimore-1, 2 to 5% LDLR Activity / Software predictions: Benign
Labcorp Genetics (formerly Invitae), Labcorp	RCV000781500	SCV000544661	pathogenic	Familial hypercholesterolemia	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 304 of the LDLR protein (p.Asp304Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 1301956, 17094996). This variant is also known as p.Asp283Glu. ClinVar contains an entry for this variant (Variation ID: 226336). 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%. Experimental studies have shown that this missense change affects LDLR function (PMID: 1301956). This variant disrupts the p.Asp304 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17094996). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000211616	SCV000583759	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Robarts Research Institute, Western University	RCV000211616	SCV000782955	likely pathogenic	Hypercholesterolemia, familial, 1	2018-01-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781500	SCV000919580	pathogenic	Familial hypercholesterolemia	2017-11-16	criteria provided, single submitter	clinical testing	Variant summary: The LDLR c.912C>G (p.Asp304Glu) variant involves the alteration of a non-conserved nucleotide that leads to the substitution of a highly conserved Asp in the ligand-binding region of the LDLR, in the class A repeat 7 domain (Interpro) where it is part of a highly conserved acidic residue motif (DXXXDXXDXXDE), corresponding to the 3rd conserved acidic residue that is involved in the proper folding of the domain through the coordinated binding of a calcium ion (Guo 2004). The variant was shown to result in a class 2B disease mechanism, i.e. causing a partial transport defect, where the LDLR protein is not properly transported from the endoplasmic reticulum to the Golgi apparatus for expression on the cell surface (Hobbs 1992). 4/5 in silico tools also predict a damaging outcome for this variant. This variant is absent in 246114 control chromosomes, but has been reported in several affected individuals (Hobbs 1992, Hooper 2012). In addition, multiple clinical diagnostic laboratories classified this variant as pathogenic/likely pathogenic. Taken together, this variant is classified as pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000826177	SCV000967716	likely pathogenic	Homozygous familial hypercholesterolemia	2018-01-19	criteria provided, single submitter	clinical testing	The p.Asp304Glu variant in LDLR has been reported in at least 3 individuals with familial hypercholesterolemia, two of which were compound heterozygotes (FH; Ho bbs 1992, Tosi 2007, Webb 1996). It has also been reported by other clinical lab oratories in ClinVar (Variation ID 226336) and is absent from large population s tudies. In vitro functional studies have shown that cultured fibroblasts from co mpound heterozygous carriers of the p.Asp304Glu variant have reduced LDLR activ ity (2-5% with c.2309-?_*2514+?del and 25-30% with p.Asp96Gly; Hobbs 1992, Webb 1996). In addition, other disease-causing variants (p.Asp304Asn, p.Asp304Tyr) a t this position have been reported in individuals with FH (Hobbs 1992, Do 2015, Loux 1992, Thormaehlen 2015, Tichy 2012, Vohnout 2016), suggesting changes at th is position are not tolerated. In summary, although additional studies are requi red to fully establish its clinical significance, the p.Asp304Glu variant is lik ely pathogenic. ACMG/AMP Criteria applied: PM2, PM5, PS3_Moderate, PS4_Supportin g (Richards 2015).
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000781500	SCV001422861	likely pathogenic	Familial hypercholesterolemia	2020-01-22	criteria provided, single submitter	curation	The p.Asp304Glu variant in LDLR has been reported in 1 European and 1 Australian individual with familial hypercholesterolemia (PMID: 22883975, 1301956), and was absent from large population studies. This variant has also been reported in ClinVar as pathogenic and likely pathogenic (Variation ID: 226336). In vitro functional studies provide some evidence that the p.Asp304Glu variant may slightly impact protein function (PMID: 1301956). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Two additional likely pathogenic variants, resulting in a different amino acid change at the same position, p.Asp304Tyr and p.Asp304Asn, have been reported in association with disease in the literature and Clinvar, supporting that a change at this position may not be tolerated (PMID: 17094996, 11845603, 1301956, 9664576, 21418584, 11810272, 12436241, 22698793, 11939787, 2088165/DOI: 10.1161/CIRCGEN.118.002192/Variation ID: 251517, 3692). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PM5, PP3, PS3_supporting, PS4_supporting (Richards 2015).
GeneDx	RCV001552501	SCV001773198	likely pathogenic	not provided	2023-10-31	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.D283E and FH Baltimore-1; This variant is associated with the following publications: (PMID: 11313767, 22883975, 33087929, 31447099, 32041611, 33303402, 34037665, 2088165, 17094996, 1301956, 9026534)
Ambry Genetics	RCV002372214	SCV002684777	pathogenic	Cardiovascular phenotype	2021-01-05	criteria provided, single submitter	clinical testing	The p.D304E pathogenic mutation (also known as c.912C>G), located in coding exon 6 of the LDLR gene, results from a C to G substitution at nucleotide position 912. The aspartic acid at codon 304 is replaced by glutamic acid, an amino acid with highly similar properties. This alteration has been reported, sometimes with p.D283E legacy nomenclature, in familial hypercholesterolemia (FH) cohorts (Heath KE et al. Eur. J. Hum. Genet. 2001;9:244-52; Hooper AJ et al. Atherosclerosis. 2012;224:430-4). It has also been detected in the compound heterozygous state in individuals with homozygous FH (Hobbs HH et al. Hum. Mutat. 1992;1:445-66; Webb JC et al. J. Lipid Res. 1996;37:368-81; Klaus G et al. Pediatr Nephrol, 2018 07;33:1199-1208). Fibroblasts from compound heterozygous patients exhibited reduced LDLR activity, but the impact of the p.D304E alteration alone was not investigated (Hobbs HH et al. Hum. Mutat. 1992;1:445-66; Webb JC et al. J. Lipid Res. 1996;37:368-81). Another alteration at the same codon, p.D304N (c.910G>A), has been detected in individuals with FH (Leitersdorf E et al. J. Clin. Invest., 1990;85:1014-23). 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.
Revvity Omics, Revvity	RCV000211616	SCV003825388	pathogenic	Hypercholesterolemia, familial, 1	2022-02-11	criteria provided, single submitter	clinical testing
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000211616	SCV000268588	pathogenic	Hypercholesterolemia, familial, 1	2008-06-10	no assertion criteria provided	clinical testing