19-11102756-T-C
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000527.5(LDLR):āc.283T>Cā(p.Cys95Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,624 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C95F) 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 | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.283T>C | p.Cys95Arg | missense_variant | 3/18 | ENST00000558518.6 | NP_000518.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.283T>C | p.Cys95Arg | missense_variant | 3/18 | 1 | NM_000527.5 | ENSP00000454071.1 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461624Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727112
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Arcensus | Feb 01, 2013 | - - |
Likely pathogenic, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
Pathogenic, no assertion criteria provided | research | Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum | - | - - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 20, 2023 | The c.283T>C (p.C95R) alteration is located in exon 3 (coding exon 3) of the LDLR gene. This alteration results from a T to C substitution at nucleotide position 283, causing the cysteine (C) at amino acid position 95 to be replaced by an arginine (R). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). 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, 2002). This particular cysteine alteration (also referred to as p.C74R) has been detected in several individuals with FH (Deiana, 2000; Fouchier, 2005; Blesa, 2006; Vandrovcova, 2013). A different variant affecting this codon (p.C95F, c.284G>T) has also been reported in association with FH (Miyake, 2009). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of LDLR class A repeat 2 (Ambry internal data). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at