rs879254427
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5
The NM_000527.5(LDLR):c.188G>A(p.Cys63Tyr) variant causes a missense, splice region 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. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C63F) has been classified as Pathogenic.
Frequency
Consequence
NM_000527.5 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.188G>A | p.Cys63Tyr | missense_variant, splice_region_variant | 2/18 | ENST00000558518.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.188G>A | p.Cys63Tyr | missense_variant, splice_region_variant | 2/18 | 1 | NM_000527.5 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Fundacion Hipercolesterolemia Familiar | Mar 01, 2016 | - - |
Likely pathogenic, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
Cardiovascular phenotype Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 17, 2021 | The p.C63Y variant (also known as c.188G>A and legacy p.C42Y), located in coding exon 2 of the LDLR gene, results from a G to A substitution at nucleotide position 188. The cysteine at codon 63 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). This particular cysteine alteration has been reported in individuals with hypercholesterolemia (Ambry internal data; Alonso R et al. Clin Biochem, 2009 Jun;42:899-903; Leren TP et al. Atherosclerosis, 2021 04;322:61-66). Two other alterations at the same codon, p.C63R (c.187T>C) and p.C63F (c.188G>T), have also been detected in individuals with hypercholesterolemia (Wang J et al. Hum Mutat, 2001 Oct;18:359; Lombardi MP et al. Genet Test, 2006;10:77-84; Rieck L et al. Clin Genet, 2020 11;98:457-467). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of the LDLR class A repeat 1 (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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