chr13-100268762-A-G
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000282.4(PCCA):āc.893A>Gā(p.Lys298Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000204 in 1,613,710 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. K298T) has been classified as Uncertain significance.
Frequency
Consequence
NM_000282.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PCCA | NM_000282.4 | c.893A>G | p.Lys298Arg | missense_variant | 11/24 | ENST00000376285.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PCCA | ENST00000376285.6 | c.893A>G | p.Lys298Arg | missense_variant | 11/24 | 1 | NM_000282.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152256Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251204Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135754
GnomAD4 exome AF: 0.0000219 AC: 32AN: 1461454Hom.: 0 Cov.: 30 AF XY: 0.0000234 AC XY: 17AN XY: 727068
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152256Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74392
ClinVar
Submissions by phenotype
Propionic acidemia Pathogenic:3Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Counsyl | Oct 03, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 16, 2023 | Variant summary: PCCA c.893A>G (p.Lys298Arg) results in a conservative amino acid change located in the Carbamoyl-phosphate synthetase large subunit-like, ATP-binding domain (IPR005479), the ATP-grasp fold domain (IPR011761), and the Biotin carboxylation domain (IPR011764) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251204 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.893A>G has been reported in the literature in at least one individual affected with Propionic Acidemia (e.g., Gallego-Villar_2013, Cammarata-Scalisi_2019, Shchelochkov_2019). At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant leads to a severe reduction in PCC activity (1.6% of wild-type activity) in vitro (e.g., Gallego-Villar_2013). Three ClinVar submitters (evaluation after 2014) have cited the variant, with two labs classifying the variant as likely pathogenic and one lab classifying it as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 06, 2024 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 06, 2017 | The K298R variant has previously been reported in an individual with propionic acidemia who was also heterozygous for a large deletion of PCCA, although the phase of these variants was not reported (Gallego-Villar et al., 2013). Functional analysis of K298R found that it is associated with 1.6% residual enzyme activity compared to wild-type (Gallego-Villar et al., 2013). The K298R variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, we interpret K298R to be a likely pathogenic variant. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at