Submissions for variant NM_000527.5(LDLR):c.534T>G (p.Asp178Glu)

dbSNP: rs879254566

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000237578	SCV000294780	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000237578	SCV000583698	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001201350	SCV000835802	pathogenic	Familial hypercholesterolemia	2024-08-07	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 178 of the LDLR protein (p.Asp178Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 11196104; Invitae). This variant is also known as p.Asp157Glu. ClinVar contains an entry for this variant (Variation ID: 251287). 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.Asp178 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 12436241, 16389549), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000237578	SCV001365634	likely pathogenic	Hypercholesterolemia, familial, 1	2020-06-04	criteria provided, single submitter	clinical testing	The p.Asp178Glu variant in LDLR (also reported at p.Asp157Glu in the literature) has been reported in at least 6 individuals with familial hypercholesterolemia (FH; Weiss 2000, Widhalm 2007, CCHMC pers comm., ClinVar Variation ID: 251287) and segregated with disease in 2 affected relatives from 1 family (CCHMC pers comm.). This variant was absent from large population studies. Computational prediction tools and conservation analyses are consistent with pathogenicity. Other variants at this position (p.Asp178Asn, p.Asn178Gly, p.Asn178His, p.Asn178Tyr, p.Asn178Val) have been reported in individuals with FH in the Human Gene Mutation Database (Stenson 2017) and in ClinVar, suggesting that changes at this position may not be tolerated. 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: PM2, PS4_Moderate, PP3, PM5_Supporting.
Institute of Human Genetics, University Hospital Muenster	RCV000237578	SCV002499683	pathogenic	Hypercholesterolemia, familial, 1	2022-04-13	criteria provided, single submitter	clinical testing	ACMG categories: PS5,PM1,PM2,PP2,PP5,BP1
Ambry Genetics	RCV002347936	SCV002641522	pathogenic	Cardiovascular phenotype	2024-11-07	criteria provided, single submitter	clinical testing	The p.D178E pathogenic mutation (also known as c.534T>G), located in coding exon 4 of the LDLR gene, results from a T to G substitution at nucleotide position 534. The aspartic acid at codon 178 is replaced by glutamic acid, an amino acid with highly similar properties. This variant (also referred to as p.D157E) has been reported in multiple individuals with features consistent with familial hypercholesterolemia (FH) (Weiss N et al. J. Inherit. Metab. Dis., 2000 Dec;23:778-90; Widhalm K et al. J. Inherit. Metab. Dis., 2007 Apr;30:239-47; Madar L et al. Genes (Basel). 2022 01;13(1); Timoshchenko O et al. Int J Mol Sci, 2023 Dec;25; external communication; Ambry internal data). Internal structural analysis indicates that this variant, which impacts a residue in the conserved cluster of acidic amino acids at the C-terminal end of LDLR class A4, is expected to have a deleterious impact on protein function (Jeon H and Blacklow C. Annu. Rev. Biochem. 2005;74:535-62; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.
Fulgent Genetics, Fulgent Genetics	RCV000237578	SCV002816928	pathogenic	Hypercholesterolemia, familial, 1	2021-11-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001201350	SCV004358483	likely pathogenic	Familial hypercholesterolemia	2022-01-03	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Asp157Glu in the mature protein) replaces aspartic acid with glutamic acid at codon 178 of the LDLR protein. This variant is located in the ligand binding domain in a region critical for LDL binding (PMID: 2600087, 3417658). Computational prediction suggests that this variant may have 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 individuals affected with familial hypercholesterolemia (PMID: 11196104, 17347910, 33418990; Shakhtshneider et al, 2019, DOI: 10.1016/j.atherosclerosis.2019.06.883). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV005404435	SCV006066432	likely pathogenic	Dyslipidemia	2020-07-17	criteria provided, single submitter	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000237578	SCV000606152	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research