ClinVar Miner

Submissions for variant NM_000282.4(PCCA):c.1430G>T (p.Gly477Val) (rs776355907)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000664973 SCV000789019 uncertain significance Propionic acidemia 2016-12-27 criteria provided, single submitter clinical testing
Invitae RCV000664973 SCV000940073 likely pathogenic Propionic acidemia 2019-09-10 criteria provided, single submitter clinical testing This sequence change replaces glycine with valine at codon 477 of the PCCA protein (p.Gly477Val). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with clinical features of propionic acidemia (PMID: 17051315, Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 550273). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). Experimental studies have shown that this missense change leads to a splicing defect (PMID: 17051315). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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