rs146013446
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4
The NM_176869.3(PPA2):c.514G>A(p.Glu172Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,606,152 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.00068 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0011 ( 0 hom. )
Consequence
PPA2
NM_176869.3 missense
NM_176869.3 missense
Scores
6
9
4
Clinical Significance
Conservation
PhyloP100: 7.81
Genes affected
PPA2 (HGNC:28883): (inorganic pyrophosphatase 2) The protein encoded by this gene is localized to the mitochondrion, is highly similar to members of the inorganic pyrophosphatase (PPase) family, and contains the signature sequence essential for the catalytic activity of PPase. PPases catalyze the hydrolysis of pyrophosphate to inorganic phosphate, which is important for the phosphate metabolism of cells. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 4-105437964-C-T is Pathogenic according to our data. Variant chr4-105437964-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 372222.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-105437964-C-T is described in Lovd as [Pathogenic]. Variant chr4-105437964-C-T is described in Lovd as [Likely_pathogenic].
BP4
Computational evidence support a benign effect (MetaRNN=0.25184813). . Strength limited to SUPPORTING due to the PP5.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PPA2 | NM_176869.3 | c.514G>A | p.Glu172Lys | missense_variant | 6/12 | ENST00000341695.10 | NP_789845.1 | |
PPA2 | NM_006903.4 | c.441+8419G>A | intron_variant | NP_008834.3 | ||||
PPA2 | NM_176866.2 | c.223-13642G>A | intron_variant | NP_789842.2 | ||||
PPA2 | NM_176867.3 | c.157+35930G>A | intron_variant | NP_789843.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000677 AC: 103AN: 152130Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000492 AC: 120AN: 243704Hom.: 0 AF XY: 0.000517 AC XY: 68AN XY: 131620
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GnomAD4 exome AF: 0.00106 AC: 1546AN: 1453904Hom.: 0 Cov.: 30 AF XY: 0.00103 AC XY: 743AN XY: 723000
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GnomAD4 genome AF: 0.000677 AC: 103AN: 152248Hom.: 0 Cov.: 32 AF XY: 0.000672 AC XY: 50AN XY: 74442
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:16
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Sudden cardiac failure, infantile Pathogenic:9
Likely pathogenic, criteria provided, single submitter | research | HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | Oct 04, 2019 | ACMG codes: PS4M, PM2, PM3 - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 25, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Centogene AG - the Rare Disease Company | Nov 16, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jul 17, 2023 | 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, 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 & v3: 221 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated pyrophosphatase domain (DECIPHER). (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. This variant has previously been reported in multiple unrelated families with PPA2-related mitochondrial disease leading to sudden cardiac arrest in both infants and adults (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) 1101 - Very strong and specific phenotype match for this individual. (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 23, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | Apr 10, 2020 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genomics Laboratory, Stanford Medicine | Jul 23, 2021 | The p.Glu172Lysvariant in the PPA2gene has been previously reported in the compound heterozygous state in many individuals affected with mitochondrial cardiomyopathy and sudden cardiac failure and segregated with disease in multiple families (Guimier et al., 2016; Kennedy et al., 2016; Vasilescu et al., 2018; Sanford et al., 2020).This variant has been identified in 120/126,898 European non-Finnish chromosomes (147/275,080 chromosomes overall) by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Functional studies of the p.Glu172Lys variant are supportive of a deleterious effect to the proteinshowing reduced enzyme activity and reduced mitochondrial maintenance and function (Guimier et al., 2016; Kennedy et al., 2016). Computational tools also predict that thisvariant is deleterious; however, the accuracy of in silicoalgorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Glu172Lys variant as pathogenic for autosomal recessive mitochondrial cardiomyopathy and sudden cardiac failure based on the information above. [ACMG evidence codes used: PM3_Very Strong; PP1_Strong; PS3; PM2; PP3] - |
Likely pathogenic, no assertion criteria provided | clinical testing | Genomics England Pilot Project, Genomics England | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 27, 2020 | 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. - |
not provided Pathogenic:5
Likely pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 23, 2024 | Published functional studies demonstrate this variant results in decreased enzyme activity (PMID: 27523597, 27523598); 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, 30384889, 27523597, 34400813, 36757698, 34587765, 35838873) - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 01, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | 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. - |
Likely pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Sudden cardiac failure, alcohol-induced Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 23, 2016 | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 24, 2022 | 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
D;T;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T
MetaSVM
Uncertain
T
MutationAssessor
Pathogenic
M;.;.
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D
REVEL
Uncertain
Sift
Uncertain
D;D;D
Sift4G
Uncertain
D;D;.
Polyphen
D;.;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at