rs771438170
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000282.4(PCCA):c.2002G>A(p.Gly668Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,802 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000282.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PCCA | NM_000282.4 | c.2002G>A | p.Gly668Arg | missense_variant | 22/24 | ENST00000376285.6 | NP_000273.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PCCA | ENST00000376285.6 | c.2002G>A | p.Gly668Arg | missense_variant | 22/24 | 1 | NM_000282.4 | ENSP00000365462 | P1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251414Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135876
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461802Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727212
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Propionic acidemia Pathogenic:5
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 07, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 21, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 668 of the PCCA protein (p.Gly668Arg). This variant is present in population databases (rs771438170, gnomAD 0.01%). This missense change has been observed in individuals with propionic acidemia (PMID: 10329019, 19099776, 27227689, 29978829). ClinVar contains an entry for this variant (Variation ID: 218266). 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 PCCA protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PCCA function (PMID: 10329019, 12385775). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | research | Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital | Jan 01, 2014 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | May 31, 2017 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jun 30, 2021 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2024 | PCCA: PM3:Very Strong, PM2, PS3:Supporting - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at