ClinVar Miner

Submissions for variant NM_176869.3(PPA2):c.380G>T (p.Arg127Leu) (rs139076647)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
RBHT Clinical Genetics and Genomics Laboratory,Royal Brompton and Harefield NHS Foundation Trust RCV000412508 SCV000845654 likely pathogenic Sudden cardiac failure, infantile 2017-09-14 criteria provided, single submitter clinical testing The c.380G>T variant is present in 48/270550 individuals in the gnomAD control population in heterozygous form, and has previously been reported in compound heterozygosity with another likely pathogenic PPA2 variant in a single infant with sudden infantile cardiac failure (Kennedy et al (2016) Am J Hum Genet 99(3):674-682). This variant was inherited from a heterozygous carrier parent. In silico analysis predicts a pathogenic effect on protein function, and the affected amino acid is highly conserved. In view of the evidence, we have interpreted this variant as likely to be pathogenic when inherited with another (likely) pathogenic variant. The c.380G>T variant is also likely to be benign when carried in isolation.
Invitae RCV001060000 SCV001224659 likely pathogenic not provided 2020-01-07 criteria provided, single submitter clinical testing This sequence change replaces arginine with leucine at codon 127 of the PPA2 protein (p.Arg127Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is present in population databases (rs139076647, ExAC 0.03%). This variant has been observed in individual(s) with clinical features of sudden cardiac failure (PMID: 27523597, 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: 372225). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
OMIM RCV000412508 SCV000490300 pathogenic Sudden cardiac failure, infantile 2016-11-23 no assertion criteria provided literature only

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