ClinVar Miner

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

gnomAD frequency: 0.00022  dbSNP: rs139076647
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Royal Brompton Clinical Genetics And Genomics Laboratory, NHS South East Genomic Laboratory Hub 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 pathogenic not provided 2024-01-08 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 127 of the PPA2 protein (p.Arg127Leu). This variant is present in population databases (rs139076647, gnomAD 0.03%). This missense change 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 being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 372225). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PPA2 protein function. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV001060000 SCV001802104 likely pathogenic not provided 2021-11-17 criteria provided, single submitter clinical testing Published functional studies demonstrate that this variant has a damaging effect on mitochondrial pyrophosphatase enzyme activity (Guimier et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; A different missense change at this residue (p.(R127C)) has been reported in association with an autosomal recessive PPA2-related disorder (Zhao et al., 2021); Reported in ClinVar as a likely pathogenic variant (ClinVar Variant ID# 372225; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 31705601, 33826954, 34400813, 27523597)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000412508 SCV002768820 pathogenic Sudden cardiac failure, infantile 2022-06-24 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with infantile sudden cardiac failure (MIM#617222). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to leucine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 44 heterozygotes, 0 homozygotes). (SP) 0309 - Two alternative amino acid changes at the same position have been observed in gnomAD (highest allele count in: v2, 12 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated pyrophosphatase domain (PDB). (I) 0708 - Other missense variants comparable to the one identified in this case have conflicting previous evidence for pathogenicity. p.(Arg127Cys) has been reported as compound heterozygous in a child with epilepsy and recurrent acute cardiac failure (PMID: 33826954), and is listed in ClinVar as a VUS. p.(Arg127His) has been reported as a VUS in ClinVar. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in five unrelated families with children suffering sudden cardiac failure during early childhood or alcohol-induced sudden cardiac arrest during their teens, and in one asymptomatic 10-year old child (PMIDs: 27523597, 31705601, 34400813). It has also been reported as likely pathogenic by multiple clinical testing laboratories (ClinVar). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Enzyme activity in the recombinant PPA2 protein harbouring R127L was significantly decreased compared to a wild-type control (PMID: 34400813). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Ambry Genetics RCV002523897 SCV003526551 uncertain significance Inborn genetic diseases 2021-07-15 criteria provided, single submitter clinical testing (Kennedy, 2016; Phoon, 2020) Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
OMIM RCV000412508 SCV000490300 pathogenic Sudden cardiac failure, infantile 2016-11-23 no assertion criteria provided literature only
Genomics England Pilot Project, Genomics England RCV000412508 SCV001760129 likely pathogenic Sudden cardiac failure, infantile no assertion criteria provided clinical testing

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