ClinVar Miner

Submissions for variant NM_176869.3(PPA2):c.514G>A (p.Glu172Lys)

gnomAD frequency: 0.00070  dbSNP: rs146013446
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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000412629 SCV001192526 likely pathogenic Sudden cardiac failure, infantile 2019-10-04 criteria provided, single submitter research ACMG codes: PS4M, PM2, PM3
Invitae RCV001060001 SCV001224660 pathogenic not provided 2024-01-29 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 172 of the PPA2 protein (p.Glu172Lys). This variant is present in population databases (rs146013446, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with clinical features of sudden cardiac failure (PMID: 27523597, 27523598, 30384889). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 372222). 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%. Experimental studies have shown that this missense change affects PPA2 function (PMID: 27523597, 27523598). For these reasons, this variant has been classified as Pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000412629 SCV001250701 pathogenic Sudden cardiac failure, infantile 2020-04-10 criteria provided, single submitter clinical testing This variant has been previously reported as a compound heterozygous change in three individuals from two families with Sudden Unexpected Cardiac Arrest in Infancy (PMID: 27523598), and in two individuals from one family who developed a rapidly progressive DCM and cardiac failure, with only a few days from disease onset to death (PMID: 30384889). Functional characterization of the variant demonstrated inactivation of the mitochondrial energy transducing system and prevention of the maintenance of a sufficient electrical potential across the inner membrane (PMID: 27523598). This glutamine to lysine substitution is at a highly conserved residue and is predicted to disrupt at least three hydrogen bonds between interacting protein chains near the surface of the enzyme's active site and subsequently impair enzymatic function of PPA2 (PMID: 27523597). This variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.053% (147/275080) and thus is presumed to be rare. Based on the available evidence, the c.514G>A (p.Glu172Lys) variant is classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000412629 SCV001653017 pathogenic Sudden cardiac failure, infantile 2020-06-27 criteria provided, single submitter clinical testing The p.Glu172Lys variant in PPA2 has been reported in the compound heterozygous state in 3 individuals with clinical features of sudden cardiac failure and segregated with disease in 5 affected relatives from 3 families (Kennedy 2016 PMID: 27523597, Guimier 2016 PMID: 27523598, Vasilescu 2018 PMID: 30384889). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 372222) and has been identified in 0.095% (120/126898) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). However, this frequency is low enough to be consistent with a recessive allele frequency. Several in vitro functional studies, including one using patient's fibroblasts, support an impact on protein function (Kennedy 2016 PMID: 27523597, Guimier 2016 PMID: 27523598, Vasilescu 2018 PMID: 30384889). Computational prediction tools and conservation analyses are consistent with pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive sudden cardiac failure in infancy. ACMG/AMP Criteria applied: PM3_Strong, PP1_Strong, PS3_Supporting, PP3.
GeneDx RCV001060001 SCV002004079 pathogenic not provided 2023-09-12 criteria provided, single submitter clinical testing Published functional studies demonstrate this variant results in decreased enzyme activity (Guimier et al., 2016; Kennedy et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34930662, 34758253, 27523598, 31705601, 30847666, 33028643, 34426522, 32917565, 27523597, 30384889, 34400813)
Revvity Omics, Revvity Omics RCV001060001 SCV002019503 pathogenic not provided 2022-11-01 criteria provided, single submitter clinical testing
Centogene AG - the Rare Disease Company RCV000412629 SCV002059821 pathogenic Sudden cardiac failure, infantile 2017-11-16 criteria provided, single submitter clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000412629 SCV002768819 pathogenic Sudden cardiac failure, infantile 2021-05-06 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as pathogenic. The following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with sudden cardiac failure, alcohol-induced (MIM#617223) and sudden cardiac failure, infantile (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 glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2) (147 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated inorganic pyrophosphatase domain (Pfam). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has previously been reported in at least 5 unrelated families with PPA2-related mitochondrial cardiomyopathy and sudden cardiac death (ClinVar; PMIDs: 27523598; 27523597; 30384889). (SP) 0901 - This variant has strong evidence for segregation with disease. This variant was shown to segregate with disease in the previously reported families (PMIDs: 27523597; 30384889). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Pyrophosphatase activity was performed using cells in which this variant was introduced into the wild-type PPA2 sequence. This resulted in a 10%-15% residual enzyme activity (PMID: 27523597). In addition, functional studies performed on patient fibroblasts demonstrated reduced steady state protein (PMID: 27523598). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Ambry Genetics RCV002524633 SCV003538764 pathogenic Inborn genetic diseases 2022-01-24 criteria provided, single submitter clinical testing The c.514G>A (p.E172K) alteration is located in exon 6 (coding exon 6) of the PPA2 gene. This alteration results from a G to A substitution at nucleotide position 514, causing the glutamic acid (E) at amino acid position 172 to be replaced by a lysine (K). Based on data from gnomAD, the A allele has an overall frequency of 0.05% (147/275080) total alleles studied. The highest observed frequency was 0.09% (120/126898) of European (non-Finnish) alleles. This mutation has been identified in several individuals with a second PPA2 variant with mitochondrial inorganic pyrophosphatase 2 deficiency and has been shown to segregate with disease in multiple families (Guimier, 2016; Kennedy, 2016; Vasilescu, 2018; Sanford, 2020; Guimier, 2021). Fibroblasts from affected individuals demonstrated a significant decrease or loss of the PPA2 protein (Guimier, 2016; Vasilescu, 2018). In E. coli, this variant demonstrated <10% residual activity compared to wildtype (Kennedy, 2016). Based on the available evidence, this alteration is classified as pathogenic.
OMIM RCV000412629 SCV000490296 pathogenic Sudden cardiac failure, infantile 2016-11-23 no assertion criteria provided literature only
OMIM RCV000412531 SCV000490297 pathogenic Sudden cardiac failure, alcohol-induced 2016-11-23 no assertion criteria provided literature only
Genomics England Pilot Project, Genomics England RCV000412629 SCV001760128 likely pathogenic Sudden cardiac failure, infantile no assertion criteria provided clinical testing
Clinical Genetics, Academic Medical Center RCV001060001 SCV001925601 likely pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV001060001 SCV001973391 likely pathogenic not provided no assertion criteria provided clinical testing

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