rs879253805
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_000282.4(PCCA):c.878A>G(p.Gln293Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,748 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000282.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461748Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5AN XY: 727188
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Propionic acidemia Pathogenic:3
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This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 293 of the PCCA protein (p.Gln293Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with propionic acidemia (PMID: 23430860, 27227689; Invitae). ClinVar contains an entry for this variant (Variation ID: 218252). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PCCA protein function with a positive predictive value of 95%. This variant disrupts the p.Gln293 amino acid residue in PCCA. Other variant(s) that disrupt this residue have been observed in individuals with PCCA-related conditions (PMID: 15164333, 23430860, 27227689), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -
not specified Uncertain:1
Variant summary: PCCA c.878A>G (p.Gln293Arg) results in a conservative amino acid change located in the Carbamoyl-phosphate synthetase large subunit-like, ATP-binding domain (IPR005479) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251330 control chromosomes (gnomAD). c.878A>G has been reported in the literature in individuals affected with Propionic Acidemia, including one homozygote (Lvesque_2011, Gupta_2016). These data indicate that the variant may be associated with disease. Additionally, another variant (p.Gln293Glu) that disrupts the same residue has been found in one individual affected with Propionic Academia, suggesting this residue is clinical important (PMID: 15164333). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -
Inborn genetic diseases Uncertain:1
The c.878A>G (p.Q293R) alteration is located in exon 11 (coding exon 11) of the PCCA gene. This alteration results from a A to G substitution at nucleotide position 878, causing the glutamine (Q) at amino acid position 293 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at