ClinVar Miner

Submissions for variant NM_176869.3(PPA2):c.346C>T (p.Pro116Ser)

gnomAD frequency: 0.00001  dbSNP: rs373735128
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
PPA2 laboratory, University of Otago RCV001638063 SCV001548254 uncertain significance Sudden cardiac failure, infantile 2021-03-02 criteria provided, single submitter research
PPA2 laboratory, University of Otago RCV001638064 SCV001548266 uncertain significance Sudden cardiac failure, alcohol-induced 2021-03-02 criteria provided, single submitter research
GeneDx RCV001773710 SCV002004072 uncertain significance not provided 2021-04-26 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Invitae RCV001773710 SCV003478493 likely pathogenic not provided 2024-01-22 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 116 of the PPA2 protein (p.Pro116Ser). This variant is present in population databases (rs373735128, gnomAD 0.009%). This missense change has been observed in individual(s) with sudden death in early childhood (PMID: 34400813). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1048573). 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 PPA2 protein function with a positive predictive value of 80%. 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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