rs879254754
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000527.5(LDLR):c.1013G>A(p.Cys338Tyr) 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. C338G) 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 rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.1013G>A | p.Cys338Tyr | missense_variant | Exon 7 of 18 | ENST00000558518.6 | NP_000518.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:4
Disrupt disulfide bridge between Cys325 and Cys338. -
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The LDLR c.1013G>A (p.Cys338Tyr) missense variant results in the substitution of cysteine at amino acid position 338 with tyrosine. This variant has been identified in individuals with a phenotype consistent with familial hypercholesterolemia, and has been shown to segregate with disease (PMID: 10924730; 34037665). A functional study conducted in patient cells demonstrated that this variant impacts protein function (PMID: 10924730). This variant affects one of 60 highly conserved cysteine residues that are critical for protein folding and function (PMID: 34906454). This variant is not observed in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Multiple lines of computational evidence suggest the variant may impact the gene or gene product. Based on the available evidence, the c.1013G>A (p.Cys338Tyr) variant is classified as likely pathogenic for familial hypercholesterolemia. -
not provided Pathogenic:1
PM1, PM5, PM2, PM3_supporting, PS3_supporting, PP3, PP1 -
Cardiovascular phenotype Pathogenic:1
The p.C338Y pathogenic mutation (also known as c.1013G>A), located in coding exon 7 of the LDLR gene, results from a G to A substitution at nucleotide position 1013. The cysteine at codon 338 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration has been reported in individuals with familial hypercholesterolemia (FH), and reduced LDL binding was demonstrated in a study of patient skin fibroblasts (Nauck MS et al. Atherosclerosis, 2000;151:525-34; Dušková L et al. Atherosclerosis, 2011;216:139-45). 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 FH (Villéger L et al. Hum Mutat. 2002;20(2):81-7). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of the EGF-like 1 domain (Rudenko G et al. Science. 2002;298(5602):2353-8). In addition, alterations at the same amino acid position (C338G, C338R, and C338S) have also been reported in association with FH (Lombardi MP et al. Clin. Genet., 2000;57:116-24; Varret M et al. Nucleic Acids Res., 1998;26:248-52; Maruyama T et al. Arterioscler. Thromb. Vasc. Biol., 1995;15:1713-8). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Familial hypercholesterolemia Pathogenic:1
This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 338 of the LDLR protein (p.Cys338Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 10924730). It has also been observed to segregate with disease in related individuals. This variant is also known as p.C317T. ClinVar contains an entry for this variant (Variation ID: 251595). 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%. Experimental studies have shown that this missense change affects LDLR function (PMID: 10924730). This variant affects a cysteine residue located within an LDLRA or epidermal-growth-factor (EGF)-like domains of the LDLR protein. Cysteine residues in these domains have been shown to be involved in the formation of disulfide bridges, which are critical for protein structure and stability (PMID: 7548065, 7603991, 7979249). In addition, missense substitutions within the LDLRA and EGF-like domains affecting cysteine residues are overrepresented among patients with hypercholesterolemia (PMID: 18325082). This variant disrupts the p.Cys338 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 8568489, 10735632, 10924730, 24420163), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at