rs879254788
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000527.5(LDLR):c.1091G>A(p.Cys364Tyr) variant causes a missense change involving the alteration of a 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. C364R) has been classified as Likely benign.
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 | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.1091G>A | p.Cys364Tyr | missense_variant | 8/18 | ENST00000558518.6 | NP_000518.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.1091G>A | p.Cys364Tyr | missense_variant | 8/18 | 1 | NM_000527.5 | ENSP00000454071 | P3 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation | Nov 05, 2016 | Disrupt disulfide bridge between Cys364 and Cys377. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Robarts Research Institute, Western University | - | - - |
Cardiovascular phenotype Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 12, 2024 | The p.C364Y variant (also known as c.1091G>A), located in coding exon 8 of the LDLR gene, results from a G to A substitution at nucleotide position 1091. The cysteine at codon 364 is replaced by tyrosine, an amino acid with highly dissimilar properties. Pathogenic LDLR mutations that result in the substitution or generation of cysteine residues within the cysteine-rich LDLR class A repeats and EGF-like domains are common in familial hypercholesterolemia (FH) (Villéger L. Hum Mutat. 2002;20(2):81-7). Internal structural analysis indicates this variant eliminates a disulfide bond critical for the structural integrity of the EGF-like 2 domain (Ambry internal data). This alteration, which is also known as p.C343Y, has been reported in individuals with FH (Wang J et al. Arterioscler Thromb Vasc Biol, 2016 Dec;36:2439-2445; Tichý L et al. Physiol Res, 2017 Apr;66:S47-S54; Pek SLT et al. Atherosclerosis, 2018 Feb;269:106-116; Sánchez-Hernández RM et al. J Clin Lipidol, 2019 May;13:618-626). Another variant at the same codon, p.C364R (c.1090T>C), has been detected in conjunction with another alteration in the LDLR gene in an individual whose protein activity was 15-30% of normal (Hobbs HH et al. Hum Mutat. 1992;1(6):445-66), and subsequent studies have reported this alteration in several individuals diagnosed with FH (Bertolini S et al. Arterioscler Thromb Vasc Biol. 2000;20(9):E41-52). 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 majority of available evidence to date, this variant is likely to be pathogenic. - |
Familial hypercholesterolemia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 29, 2020 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys364 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1301956, 23375686, 26723464, 21722902, 25461735, 16314194, 10978268, 15556094). 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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individual(s) with familial hypercholesterolemia (PMID: 31153816, 29353225, 27765764, 28379029). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 369852). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with tyrosine at codon 364 of the LDLR protein (p.Cys364Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at