ClinVar Miner

Submissions for variant NM_000282.4(PCCA):c.412G>A (p.Ala138Thr)

dbSNP: rs202247814
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000032110 SCV004099977 pathogenic Propionic acidemia 2023-09-19 criteria provided, single submitter clinical testing Variant summary: PCCA c.412G>A (p.Ala138Thr) results in a non-conservative amino acid change located in the Biotin carboxylase-like, N-terminal domain (IPR005481) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251356 control chromosomes (gnomAD). c.412G>A (also known as p.Ala113Thr) has been reported in the literature in individuals affected with Propionic Acidemia (examples: Richard_1997, Perez-Cerda_2000, Nizon_2013). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Perez-Cerda_2000). The following publications have been ascertained in the context of this evaluation (PMID: 32778825, 24059531, 10780784, 10101253). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV000032110 SCV004202874 likely pathogenic Propionic acidemia 2023-06-19 criteria provided, single submitter clinical testing
Invitae RCV000032110 SCV004296510 pathogenic Propionic acidemia 2023-09-25 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 138 of the PCCA protein (p.Ala138Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with propionic acidemia (PMID: 10101253; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as p.Ala113Thr. ClinVar contains an entry for this variant (Variation ID: 38867). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects PCCA function (PMID: 12385775). For these reasons, this variant has been classified as Pathogenic.
GeneReviews RCV000032110 SCV000055650 not provided Propionic acidemia no assertion provided literature only

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