Submissions for variant NM_000527.5(LDLR):c.268G>T (p.Asp90Tyr)

dbSNP: rs749038326

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000237660	SCV001960913	likely pathogenic	Hypercholesterolemia, familial, 1	2021-06-07	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.268G>T (p.Asp90Tyr) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM5_Strong, PM2, 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: PM5_Strong - Four more missense variants described in same codon: --- 3 variants classified as Pathogenic, so PM5_Strong is Met. PM2 - No population data was found for this variant in gnomAD (gnomAD v2.1.1). PM5 - Four more missense variants described in same codon, 3 variants classified as Pathogenic, so PM5 is Met. PP3 - REVEL = 0.958. It is above 0.75, so PP3 is Met. PP4 - Variant meets PM2. Identified in 1 index case who fulfills Simon-Broome criteria from Center of molecular biology and gene therapy.
LDLR-LOVD, British Heart Foundation	RCV000237660	SCV000294570	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	RCV000237660	SCV000540722	likely pathogenic	Hypercholesterolemia, familial, 1	2016-11-05	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001857821	SCV002282209	likely pathogenic	Familial hypercholesterolemia	2023-03-07	criteria provided, single submitter	clinical testing	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: 251106). This variant is also known as FH Durban-1 and asp69tyr. This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 8347689). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 90 of the LDLR protein (p.Asp90Tyr). 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: 12837857, 16343504, 21376320, 25962062). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
All of Us Research Program, National Institutes of Health	RCV000237660	SCV004830222	likely pathogenic	Hypercholesterolemia, familial, 1	2023-06-08	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Asp69Tyr in the mature protein) replaces aspartic acid with tyrosine at codon 90 in the second LDLR type A of the ligand binding domain of the LDLR protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with familial hypercholesterolemia (PMID: 34456200). This variant has also been reported in compound heterozygous state in individuals affected with homozygous familial hypercholesterolemia (PMID: 8347689). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different variants occurring at the same codon (p.Asp90Asn, p.Asp90Gly, p.Asp90Glu, p.Asp90Ala), are well documented pathogenic mutations (ClinVar variation IDs: 215505, 226313, 251107, 440555), indicating that aspartic acid at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Likely Pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV000237660	SCV005438953	likely pathogenic	Hypercholesterolemia, familial, 1	2023-07-22	criteria provided, single submitter	clinical testing	The missense c.268G>T p.Asp90Tyr variant in the LDLR gene has been observed in individuals with familial hypercholesterolemia Rubinsztein, D C et al., 1993. Other variants that disrupt this residue have been determined to be pathogenic Han, Soo Min et al., 2015. The variant is absent in gnomAD Exomes. It is submitted to ClinVar as Likely Pathogenic reviewed by expert panel. The amino acid Aspartic acid at position 90 is changed to a Tyrosine changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence Polyphen - Damaging, SIFT – Damaging and MutationTaster - Disease causing predict a damaging effect on protein structure and function for this variant. The amino acid Aspartic acid in LDLR is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic.
Ambry Genetics	RCV004992112	SCV005609302	pathogenic	Cardiovascular phenotype	2024-07-22	criteria provided, single submitter	clinical testing	The p.D90Y pathogenic mutation (also known as c.268G>T), located in coding exon 3 of the LDLR gene, results from a G to T substitution at nucleotide position 268. The aspartic acid at codon 90 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration, which is also known as p.D69Y, has been reported in individuals with concerns for familial hypercholesterolemia (FH), including being identified in trans with another alteration in LDLR in an individual with homozygous FH (Rubinsztein DC et al. Biochim Biophys Acta, 1993 Aug;1182:75-82; Kim H et al. J Atheroscler Thromb, 2022 Aug;29:1176-1187; Ambry internal data). Another variant at the same codon, p.D90N (c.268G>A), has been detected in multiple individuals with FH and in FH cohorts from a variety of ethnic backgrounds (Day IN et al. Hum. Mutat., 1997;10:116-27; Mak YT et al. Arterioscler. Thromb. Vasc. Biol., 1998 Oct;18:1600-5; Khoo KL et al. Clin. Genet., 2000 Aug;58:98-105; Chang JH et al. J. Lipid Res., 2003 Oct;44:1850-8; Fouchier SW et al. Hum. Mutat., 2005 Dec;26:550-6; Norsworthy PJ et al. BMC Med. Genet., 2014 Jun;15:70). 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 variant is interpreted as a disease-causing mutation.