ACMG codes: PS4M, PM2, PM3
ClinVar Genomic variation as it relates to human health
NM_176869.3(PPA2):c.514G>A (p.Glu172Lys)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(16)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
16
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_176869.3(PPA2):c.514G>A (p.Glu172Lys)
Variation ID: 372222 Accession: VCV000372222.32
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 4q24 4: 105437964 (GRCh38) [ NCBI UCSC ] 4: 106359121 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jan 7, 2017 Sep 29, 2024 Mar 25, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_176869.3:c.514G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_789845.1:p.Glu172Lys missense NM_006903.4:c.441+8419G>A intron variant NM_176866.2:c.223-13642G>A intron variant NM_176867.3:c.157+35930G>A intron variant NC_000004.12:g.105437964C>T NC_000004.11:g.106359121C>T NG_053007.1:g.41107G>A - Protein change
- E172K
- Other names
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p.Glu172Lys
- Canonical SPDI
- NC_000004.12:105437963:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00020 (T)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
1000 Genomes Project 0.00020
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00046
Exome Aggregation Consortium (ExAC) 0.00049
The Genome Aggregation Database (gnomAD), exomes 0.00049
1000 Genomes Project 30x 0.00016
Trans-Omics for Precision Medicine (TOPMed) 0.00054
The Genome Aggregation Database (gnomAD) 0.00070
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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| PPA2 | - | - |
GRCh38 GRCh37 |
352 | 373 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (1) |
no assertion criteria provided
|
Nov 23, 2016 | RCV000412531.3 | |
| Pathogenic/Likely pathogenic (9) |
criteria provided, multiple submitters, no conflicts
|
Mar 25, 2024 | RCV000412629.16 | |
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Mar 13, 2024 | RCV001060001.17 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 24, 2022 | RCV002524633.3 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely pathogenic
(Oct 04, 2019)
|
criteria provided, single submitter
Method: research
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Sudden cardiac failure, infantile
Affected status: yes
Allele origin:
maternal
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HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Study: CSER-SouthSeq
Accession: SCV001192526.1 First in ClinVar: Mar 29, 2020 Last updated: Mar 29, 2020 |
Comment:
ACMG codes: PS4M, PM2, PM3
Number of individuals with the variant: 1
Clinical Features:
Intrauterine growth retardation (present) , Small for gestational age (present) , Congenital microcephaly (present) , Corpus callosum agenesis (present) , Hand clenching (present) , Abnormality … (more)
Intrauterine growth retardation (present) , Small for gestational age (present) , Congenital microcephaly (present) , Corpus callosum agenesis (present) , Hand clenching (present) , Abnormality of brain morphology (present) , Ventriculomegaly (present) (less)
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Pathogenic
(Apr 10, 2020)
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criteria provided, single submitter
Method: clinical testing
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Sudden cardiac failure, infantile
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
paternal
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Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV001250701.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
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: … (more)
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. (less)
Sex: male
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Pathogenic
(Jun 27, 2020)
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criteria provided, single submitter
Method: clinical testing
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Sudden cardiac failure, infantile
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV001653017.1
First in ClinVar: May 29, 2021 Last updated: May 29, 2021 |
Comment:
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 … (more)
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. (less)
Number of individuals with the variant: 1
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Pathogenic
(Nov 16, 2017)
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criteria provided, single submitter
Method: clinical testing
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Sudden cardiac failure, infantile
Affected status: no
Allele origin:
germline
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Centogene AG - the Rare Disease Company
Accession: SCV002059821.1
First in ClinVar: Jan 14, 2022 Last updated: Jan 14, 2022 |
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Pathogenic
(Nov 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002019503.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 29, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001224660.4
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
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 … (more)
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. (less)
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Likely pathogenic
(Mar 25, 2024)
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criteria provided, single submitter
Method: clinical testing
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Sudden cardiac failure, infantile
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004806293.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
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Pathogenic
(Jan 24, 2022)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV003538764.2
First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Jul 23, 2021)
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criteria provided, single submitter
Method: clinical testing
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Sudden cardiac failure, infantile
Affected status: yes
Allele origin:
germline
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Clinical Genomics Laboratory, Stanford Medicine
Accession: SCV005062005.1
First in ClinVar: Jul 07, 2024 Last updated: Jul 07, 2024 |
Comment:
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 … (more)
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] (less)
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Pathogenic
(Jul 17, 2023)
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criteria provided, single submitter
Method: clinical testing
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Sudden cardiac failure, infantile
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002768819.2
First in ClinVar: Dec 24, 2022 Last updated: Jul 23, 2024 |
Comment:
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 … (more)
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 (less)
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Pathogenic
(Mar 13, 2024)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV002004079.5
First in ClinVar: Nov 06, 2021 Last updated: Sep 29, 2024 |
Comment:
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 … (more)
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) (less)
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Pathogenic
(Nov 23, 2016)
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no assertion criteria provided
Method: literature only
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SUDDEN CARDIAC FAILURE, ALCOHOL-INDUCED
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000490297.2
First in ClinVar: Jan 07, 2017 Last updated: Jan 07, 2017 |
Comment on evidence:
Sudden Cardiac Failure, Infantile In 3 deceased children from 2 unrelated families with infantile sudden cardiac failure (SCFI; 617222), Guimier et al. (2016) identified compound … (more)
Sudden Cardiac Failure, Infantile In 3 deceased children from 2 unrelated families with infantile sudden cardiac failure (SCFI; 617222), Guimier et al. (2016) identified compound heterozygosity for 2 mutations in the PPA2 gene: a c.514G-A transition (rs146013446), resulting in a glu172-to-lys (E172K) substitution at a highly conserved residue within the pyrophosphatase domain, and another missense mutation, also within the pyrophosphatase domain: in the first family, the second mutation was a c.280A-G transition, resulting in a met94-to-val (M94V; 609988.0004) substitution, and in the second family, the second mutation was a c.318G-T transversion, resulting in a met106-to-ile (M106I; 609988.0005) substitution. All 3 mutations segregated with disease in the respective families. Two infants died at 4 months of age and the other at age 20 months. Functional analysis in yeast demonstrated a significant (60%) decrease in oxygen consumption, and thus in mitochondrial ATP synthesis as well, with the E172K mutant compared to wildtype. In addition, the mutant prevented the maintenance of an electrical potential across the mitochondrial inner membrane. In an Irish boy who died at age 2 years from sudden cardiac failure, Kennedy et al. (2016) identified compound heterozygosity for the E172K mutation and a c.380C-T transition in the PPA2 gene, resulting in an arg127-to-leu (R127L; 609988.0006) substitution at a highly conserved residue. His parents were each heterozygous for 1 of the mutations, both of which were present in the ExAC database (December 2015) at a frequency of less than 0.005: the E172K variant was found in 59/60,400 individuals, and the R127L variant in 20/60,677 individuals. However, neither mutation was found in homozygous state in 7,000 control in-house exomes or in the ExAC or NHLBI Exome Variant Server (ESP6500) databases. Heart autopsy specimens showed decreased PPA2 levels as well as decreased levels of the complex I structural protein NDUFS4 (602694), consistent with the observed decrease in complex I activity in heart tissue. Pyrophosphatase activity assay using recombinant PPA2 expressed in E. coli showed 5 to 10% residual activity with the E172K mutant compared to wildtype. Sudden Cardiac Failure, Alcohol-Induced In 4 affected sibs from a Caucasian New Zealand family with alcohol-induced sudden cardiac failure (SCFAI; 617223), Kennedy et al. (2016) identified compound heterozygosity for the E172K mutation and a c.683C-T transition, resulting in a pro228-to-leu (P228L; 609988.0008) substitution at a highly conserved residue. Their parents were each heterozygous for 1 of the mutations, and the P228L variant was also present in the ExAC database (December 2015) in 30 of 60,134 individuals (minor allele frequency of less than 0.005), but was not found in homozygous state in 7,000 control in-house exomes or in the ExAC or NHLBI Exome Variant Server (ESP6500) databases. Pyrophosphatase activity assay using recombinant PPA2 expressed in E. coli showed 24 to 28% residual activity with the P228L mutant compared to wildtype, whereas the E172K mutant had residual activity of only 5 to 10%. In this family, 2 brothers died at ages 15 years and 20 years after ingestion of small amounts of alcohol, whereas the remaining brother and sister were alive and asymptomatic at ages 33 years and 38 years despite marked mid-myocardial fibrosis on cardiac MRI. (less)
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Pathogenic
(Nov 23, 2016)
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no assertion criteria provided
Method: literature only
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SUDDEN CARDIAC FAILURE, INFANTILE
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000490296.2
First in ClinVar: Jan 07, 2017 Last updated: Jan 07, 2017 |
Comment on evidence:
Sudden Cardiac Failure, Infantile In 3 deceased children from 2 unrelated families with infantile sudden cardiac failure (SCFI; 617222), Guimier et al. (2016) identified compound … (more)
Sudden Cardiac Failure, Infantile In 3 deceased children from 2 unrelated families with infantile sudden cardiac failure (SCFI; 617222), Guimier et al. (2016) identified compound heterozygosity for 2 mutations in the PPA2 gene: a c.514G-A transition (rs146013446), resulting in a glu172-to-lys (E172K) substitution at a highly conserved residue within the pyrophosphatase domain, and another missense mutation, also within the pyrophosphatase domain: in the first family, the second mutation was a c.280A-G transition, resulting in a met94-to-val (M94V; 609988.0004) substitution, and in the second family, the second mutation was a c.318G-T transversion, resulting in a met106-to-ile (M106I; 609988.0005) substitution. All 3 mutations segregated with disease in the respective families. Two infants died at 4 months of age and the other at age 20 months. Functional analysis in yeast demonstrated a significant (60%) decrease in oxygen consumption, and thus in mitochondrial ATP synthesis as well, with the E172K mutant compared to wildtype. In addition, the mutant prevented the maintenance of an electrical potential across the mitochondrial inner membrane. In an Irish boy who died at age 2 years from sudden cardiac failure, Kennedy et al. (2016) identified compound heterozygosity for the E172K mutation and a c.380C-T transition in the PPA2 gene, resulting in an arg127-to-leu (R127L; 609988.0006) substitution at a highly conserved residue. His parents were each heterozygous for 1 of the mutations, both of which were present in the ExAC database (December 2015) at a frequency of less than 0.005: the E172K variant was found in 59/60,400 individuals, and the R127L variant in 20/60,677 individuals. However, neither mutation was found in homozygous state in 7,000 control in-house exomes or in the ExAC or NHLBI Exome Variant Server (ESP6500) databases. Heart autopsy specimens showed decreased PPA2 levels as well as decreased levels of the complex I structural protein NDUFS4 (602694), consistent with the observed decrease in complex I activity in heart tissue. Pyrophosphatase activity assay using recombinant PPA2 expressed in E. coli showed 5 to 10% residual activity with the E172K mutant compared to wildtype. Sudden Cardiac Failure, Alcohol-Induced In 4 affected sibs from a Caucasian New Zealand family with alcohol-induced sudden cardiac failure (SCFAI; 617223), Kennedy et al. (2016) identified compound heterozygosity for the E172K mutation and a c.683C-T transition, resulting in a pro228-to-leu (P228L; 609988.0008) substitution at a highly conserved residue. Their parents were each heterozygous for 1 of the mutations, and the P228L variant was also present in the ExAC database (December 2015) in 30 of 60,134 individuals (minor allele frequency of less than 0.005), but was not found in homozygous state in 7,000 control in-house exomes or in the ExAC or NHLBI Exome Variant Server (ESP6500) databases. Pyrophosphatase activity assay using recombinant PPA2 expressed in E. coli showed 24 to 28% residual activity with the P228L mutant compared to wildtype, whereas the E172K mutant had residual activity of only 5 to 10%. In this family, 2 brothers died at ages 15 years and 20 years after ingestion of small amounts of alcohol, whereas the remaining brother and sister were alive and asymptomatic at ages 33 years and 38 years despite marked mid-myocardial fibrosis on cardiac MRI. (less)
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
|
Sudden cardiac failure, infantile
Affected status: yes
Allele origin:
germline
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Genomics England Pilot Project, Genomics England
Accession: SCV001760128.1
First in ClinVar: Jul 27, 2021 Last updated: Jul 27, 2021 |
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001925601.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001973391.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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Comment:
Comment:
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.
Comment:
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.
Comment:
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.
Comment:
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.
Comment:
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]
Comment:
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
Comment:
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)
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
ACMG codes: PS4M, PM2, PM3
Comment:
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.
Comment:
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.
Comment:
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.
Comment:
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.
Comment:
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]
Comment:
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
Comment:
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)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families. | Guimier A | Genetics in medicine : official journal of the American College of Medical Genetics | 2021 | PMID: 34400813 |
| Postmortem diagnosis of PPA2-associated sudden cardiac death from dried blood spot in a neonate presenting with vocal cord paralysis. | Sanford E | Cold Spring Harbor molecular case studies | 2020 | PMID: 33028643 |
| Genetic Basis of Severe Childhood-Onset Cardiomyopathies. | Vasilescu C | Journal of the American College of Cardiology | 2018 | PMID: 30384889 |
| Biallelic PPA2 Mutations Cause Sudden Unexpected Cardiac Arrest in Infancy. | Guimier A | American journal of human genetics | 2016 | PMID: 27523598 |
| Sudden Cardiac Death Due to Deficiency of the Mitochondrial Inorganic Pyrophosphatase PPA2. | Kennedy H | American journal of human genetics | 2016 | PMID: 27523597 |
Text-mined citations for rs146013446 ...
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Record last updated Oct 08, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.