Submissions for variant NM_000527.5(LDLR):c.270T>A (p.Asp90Glu)

dbSNP: rs372828849

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000238563	SCV002506340	pathogenic	Hypercholesterolemia, familial, 1	2021-12-30	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.270T>A (p.Asp90Glu) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence PP1_Strong, PM2, PM5, PP3, PP4 and PS4_Supporting 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: PP1_strong - variant segregates with FH phenotype in 11 informative meiosis from 2 families from PMID 20809525 (Marduel et al., 2010): F1: 4 affected relatives have the variant and 3 unaffected relatives do not have the variant; F2: 3 affected relatives have the variant and 1 unaffected relative does not have the variant, so PP1_Strong is met. PM2 - This variant was not identified in gnomAD (gnomAD v2.1.1), so PM2 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.269A>G (p.Asp90Gly) - Pathogenic by these guidelines There is 1 variant classified as Pathogenic by these guidelines, so PM5 is met. PP3 - REVEL = 0.833. It is above 0.75, so PP3 is met. PP4 - variant meets PM2 and was identified in 4 index cases with SB criteria of FH (total and LDL-cholesterol levels above the 95th percentile of a sex and age-matched French population and autosomal dominant transmission of hypercholesterolemia in the family) from PMID 20809525 (Marduel et al., 2010), so PP4 is met. PS4_supporting - variant meets PM2 and was identified in 4 index cases with SB criteria of FH from PMID 20809525 (Marduel et al., 2010), (see PP4 for details), so PS4_Supporting is met.
LDLR-LOVD, British Heart Foundation	RCV000238563	SCV000294572	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	RCV000238563	SCV000503124	pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subject mutated among 2600 FH index cases screened = 1 , family members = 8 with co-segregation / other mutations at same codon / Software predictions: Damaging
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000238563	SCV000583647	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Invitae	RCV001057934	SCV001222461	likely pathogenic	Familial hypercholesterolemia	2019-12-24	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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: 25962062, 21376320, 27765764, 15823276, 16343504, 12837857, 12436241, 11857755, 9026534). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) with familial hypercholesterolemia (PMID: 20809525, 27824480, Invitae). ClinVar contains an entry for this variant (Variation ID: 251107). This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with glutamic acid at codon 90 of the LDLR protein (p.Asp90Glu). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and glutamic acid.
Ambry Genetics	RCV002429168	SCV002740989	pathogenic	Cardiovascular phenotype	2015-04-03	criteria provided, single submitter	clinical testing	The p.D90E pathogenic mutation (also known as c.270T>A), located in coding exon 3 of the LDLR gene, results from a T to A substitution at nucleotide position 270. The aspartic acid at codon 90 is replaced by glutamic acid, an amino acid with highly similar properties. This pathogenic mutation was described in four probands with total cholesterol and LDL-cholesterol levels above the 95th percentile and a family history of hypercholesterolemia. This alteration was found to segregate with disease in multiple individuals ( Marduel M, Hum. Mutat. 2010; 31(11):E1811-24). Other described pathogenic alterations, p.D90A, p.D90G, p.D90N and p.D90Y, have been described in this same codon. Based on the supporting evidence, p.D90E is interpreted as a disease-causing mutation.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000238563	SCV000606059	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research