rs879254566
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000527.5(LDLR):c.534T>G(p.Asp178Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D178G) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000527.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.534T>G | p.Asp178Glu | missense_variant | 4/18 | ENST00000558518.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.534T>G | p.Asp178Glu | missense_variant | 4/18 | 1 | NM_000527.5 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Cov.: 33
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:6
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 04, 2020 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University Hospital Muenster | Apr 13, 2022 | ACMG categories: PS5,PM1,PM2,PP2,PP5,BP1 - |
Pathogenic, no assertion criteria provided | research | Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Nov 12, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille | Mar 30, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
Familial hypercholesterolemia Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 03, 2022 | 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. - |
Cardiovascular phenotype Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 30, 2020 | The p.D178E variant (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 described as legacy p.D157E, has been reported in individuals with familial hypercholesterolemia (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). This alteration impacts a residue in the conserved cluster of acidic amino acids at the C-terminal end of LDLR class A repeat 4 (Jeon H and Blacklow C. Annu. Rev. Biochem. 2005;74:535-62). Based on internal structural analysis, this variant is highly destabilizing to the local structure (Guttman M et al. Biochemistry, 2011 Dec;50:11001-8). 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 majority of available evidence to date, this variant is likely to be pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at