Submissions for variant NM_000527.5(LDLR):c.269A>G (p.Asp90Gly)

dbSNP: rs771019366

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000211676	SCV002506339	pathogenic	Hypercholesterolemia, familial, 1	2021-12-30	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.269A>G (p.Asp90Gly) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PS4, PP1_Moderate, PM2, PM3, PM5, 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: PS4 - variant meets PM2 and was identified in at least 14 unrelated index cases with clinical criteria of FH: - 4 unrelated index cases with DLCN >=6 from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA), Australia; - at least 1 index case with DLCN probable FH from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille (SCV000583646.1), France; - 8 unrelated index cases (7 with DLCN>=6 and 1 SB possible) from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière), France; - at least 1 index case with SB criteria for FH (plasma cholesterol of >8.0 mmol/L and family histories of hypercholesterolemia and/or classical clinical stigmata of FH) from PMID 11857755 (Bunn et al., 2002), New Zeland; - 1 index case with SB criteria for FH (grossly increased plasma cholesterol concentration and the presence of xanthomata in childhood and cardiovascular involvement by puberty in the proband, together with hypercholesterolemia in both parents; this index case died at 31years, had cholesterol of 20.7mmol/L and CVD) from PMID 9026534 (Webb et al., 1996), UK so PS4 is met. PP1_moderate - Variant segregates with FH phenotype in 5 informative meiosis from 3 families: - 2 affected family members have the variant, from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA); - 3 affected family members have the variant, from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière), so PP1_Moderate is met. PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met. PM3 - variant meets PM2 and was identified in - 1 index case with phenotype of homozygous FH (cholesterol of 20.7mmol/L) and also NM_000527.5(LDLR):c.912C>G (p.Asp304Glu), Likely pathogenic by these guidelines, from PMID 9026534 (Webb et al., 1996), UK so PM3 is met PM5 - 4 other missense variants is the same codon: - NM_000527.5(LDLR):c.268G>A (p.Asp90Asn) - Likely pathogenic by these guidelines - NM_000527.5(LDLR):c.268G>T (p.Asp90Tyr) - classified as Likely pathogenic by the FH VCEP, with these guidelines - NM_000527.5(LDLR):c.269A>C (p.Asp90Ala) - Likely pathogenic by these guidelines - NM_000527.5(LDLR):c.270T>A (p.Asp90Glu) - Pathogenic by these guidelines There is 1 variant classified as Pathogenic by these guidelines, so PM5 is met. PP3 - REVEL = 0.957. It is above 0.75, so PP3 is met PP4 - variant meets PM2 and was identified in at least 14 unrelated index cases with clinical criteria of FH (see PS4 for details), so PP4 is met
LDLR-LOVD, British Heart Foundation	RCV000211676	SCV000294571	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	RCV000211676	SCV000503123	pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subjects mutated among 2600 FH index cases screened = 8 , family members = 5 with co-segregation / FH-London-4, 15 to 30% LDLR activity / Software predictions: Damaging
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000211676	SCV000583646	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000844733	SCV000732011	likely pathogenic	Homozygous familial hypercholesterolemia	2017-10-23	criteria provided, single submitter	clinical testing	The p.Asp90Gly variant in LDLR has been reported in 5 individuals with familial hypercholesterolemia (FH: 4 in the heterozygous state, 1 in the homozygous state ; Hobbs 1992, Amsellem 2002, Bunn 2002, Do 2015). This variant has also been rep orted in ClinVar (Variation ID# 226313) with one submission (SCV000503124.1) quo ting co-segregation with disease. In vitro functional studies provide some evide nce that the p.Asp90Gly variant may impact protein function (Hobbs 1992). This v ariant has also been identified in 1/66740 European chromosomes by the Exome Agg regation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs771019366). T his frequency is low enough to be consistent with the frequency of FH in the gen eral population. Computational prediction tools and conservation analysis sugges t that the p.Asp90Gly variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Other missense variants at t his position have been reported in individuals with hypercholesterolemia (HGMD d atabase, Stenson 2017). In summary, although additional studies are required to fully establish its clinical significance, the p.Asp90Gly variant is likely pat hogenic. ACMG/AMP Criteria applied: PM2; PM5_supporting; PP3; PS3_Supporting; PS 4_Supporting (Richards 2015).
Invitae	RCV002229194	SCV000823749	pathogenic	Familial hypercholesterolemia	2023-08-04	criteria provided, single submitter	clinical testing	This missense change has been observed in individuals with autosomal dominant or autosomal recessive familial hypercholesterolemia (PMID: 1301956, 9026534, 9259195, 11857755, 12436241, 19837725). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asp90 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8347689, 12837857, 15823276, 16343504, 19026292, 20809525, 21376320, 25962062, 27765764, 27824480). 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: 226313). This variant is also known as p.Asp69Gly. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 90 of the LDLR protein (p.Asp90Gly).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002229194	SCV002600683	pathogenic	Familial hypercholesterolemia	2022-10-23	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.269A>G (p.Asp90Gly) results in a non-conservative amino acid change located in the Low-density lipoprotein (LDL) receptor class A repeat (IPR002172) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251490 control chromosomes (gnomAD). c.269A>G has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (e.g. Day_1997, Hooper_2012, Elfatih_2021). These data indicate that the variant is very likely to be associated with disease. Six ClinVar submitters, including one expert panel (ClinGen FH expert panel), have assessed the variant since 2014: two classified the variant as likely pathogenic, and four (including the expert panel) classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics	RCV002426991	SCV002743473	pathogenic	Cardiovascular phenotype	2022-10-11	criteria provided, single submitter	clinical testing	The p.D90G pathogenic mutation (also known as c.269A>G), located in coding exon 3 of the LDLR gene, results from an A to G substitution at nucleotide position 269. The aspartic acid at codon 90 is replaced by glycine, an amino acid with similar properties. This alteration, also known as FH London-4 and D69G, has been reported in hypercholesterolemia patients from various ethnic groups (Hobbs HH et al. Hum. Mutat., 1992;1:445-66; Webb JC et al. J. Lipid Res., 1996 Feb;37:368-81; Day IN et al. Hum. Mutat., 1997;10:116-27; Bunn CF et al. Hum. Mutat., 2002 Mar;19:311; Amsellem S et al. Hum. Genet., 2002 Dec;111:501-10; Hooper AJ et al. Atherosclerosis, 2012 Oct;224:430-4). Other alterations at the same codon, p.D90N and p.D90E, have also reported in association with hypercholesterolemia (Day IN et al. Hum. Mutat., 1997;10:116-27; Marduel M et al. Hum. Mutat., 2010 Nov;31:E1811-24). Based on internal structural analysis, this variant is predicted to be structurally disruptive (Kurniawan ND et al. Protein Sci. 2000 Jul;9(7):1282-93). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	RCV000211676	SCV003827180	pathogenic	Hypercholesterolemia, familial, 1	2022-09-24	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003417768	SCV004113006	pathogenic	LDLR-related condition	2022-10-26	criteria provided, single submitter	clinical testing	The LDLR c.269A>G variant is predicted to result in the amino acid substitution p.Asp90Gly. This variant is also described using legacy nomenclature as p.Asp69Gly, has been well-documented to be pathogenic for Hypercholesterolemia (Hobbs et al. 1992. PubMed ID: 1301956; Webb et al. 1996. PubMed ID: 9026534; Day et al. 1997. PubMed ID: 9259195; Amsellem et al. 2002. PubMed ID: 12436241; Sturm et al. 2021. PubMed ID: 34037665). This variant have also been interpreted as pathogenic by the Hypercholesterolemia Variant Curation Expert Panel (https://erepo.clinicalgenome.org/evrepo/ui/interpretation/243fe145-86fd-48f6-98dd-c946485388c0). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000211676	SCV000268549	pathogenic	Hypercholesterolemia, familial, 1	2008-06-05	no assertion criteria provided	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000211676	SCV000606058	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research