13-100268732-G-A
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000282.4(PCCA):c.863G>A(p.Arg288Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,248 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R288G) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000282.4 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 |
---|---|---|---|---|---|---|---|
PCCA | NM_000282.4 | c.863G>A | p.Arg288Lys | missense_variant | 11/24 | ENST00000376285.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PCCA | ENST00000376285.6 | c.863G>A | p.Arg288Lys | missense_variant | 11/24 | 1 | NM_000282.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152248Hom.: 0 Cov.: 33
GnomAD4 exome Cov.: 30
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152248Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74394
ClinVar
Submissions by phenotype
Propionic acidemia Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 07, 2023 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg288 amino acid residue in PCCA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20493181). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PCCA protein function. ClinVar contains an entry for this variant (Variation ID: 218262). This missense change has been observed in individual(s) with propionic acidemia (PMID: 27227689; Invitae). This variant is present in population databases (no rsID available, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 288 of the PCCA protein (p.Arg288Lys). - |
Pathogenic, criteria provided, single submitter | research | Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital | Jan 01, 2014 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at