rs146013446

Positions:

chr4-105437964-C-T

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

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16

Conservation

PhyloP100: 7.81

Variant links:

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]

PPA2 links:

Genome browser will be placed here

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 link	c.514G>A	p.Glu172Lys	missense_variant	6/12	ENST00000341695.10	NP_789845.1	Q9H2U2-1
PPA2	NM_006903.4 link	c.441+8419G>A		intron_variant			NP_008834.3	Q9H2U2-3
PPA2	NM_176866.2 link	c.223-13642G>A		intron_variant			NP_789842.2	Q9H2U2-6
PPA2	NM_176867.3 link	c.157+35930G>A		intron_variant			NP_789843.2	Q9H2U2-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPA2	ENST00000341695.10 link	c.514G>A	p.Glu172Lys	missense_variant	6/12	1	NM_176869.3	ENSP00000343885.5		Q9H2U2-1

Frequencies

GnomAD3 genomes

AF:

0.000677

AC:

103

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00142

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00106

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000492

AC:

120

AN:

243704

Hom.:

AF XY:

0.000517

AC XY:

AN XY:

131620

show subpopulations

Gnomad AFR exome

AF:

0.000187

Gnomad AMR exome

AF:

0.0000610

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000211

Gnomad FIN exome

AF:

0.000374

Gnomad NFE exome

AF:

0.000888

Gnomad OTH exome

AF:

0.000339

GnomAD4 exome

AF:

0.00106

AC:

1546

AN:

1453904

Hom.:

Cov.:

AF XY:

0.00103

AC XY:

743

AN XY:

723000

show subpopulations

Gnomad4 AFR exome

AF:

0.000335

Gnomad4 AMR exome

AF:

0.0000467

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000155

Gnomad4 FIN exome

AF:

0.000696

Gnomad4 NFE exome

AF:

0.00128

Gnomad4 OTH exome

AF:

0.000965

GnomAD4 genome

AF:

0.000677

AC:

103

AN:

152248

Hom.:

Cov.:

AF XY:

0.000672

AC XY:

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.000193

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.00142

Gnomad4 NFE

AF:

0.00106

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000712

Hom.:

Bravo

AF:

0.000540

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000486

AC:

EpiCase

AF:

0.000711

EpiControl

AF:

0.000775

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

0.040

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.55

D;T;T

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Benign

0.037

MetaRNN

Benign

0.25

T;T;T

MetaSVM

Uncertain

-0.013

MutationAssessor

Pathogenic

3.5

M;.;.

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-3.5

D;D;D

REVEL

Uncertain

0.51

Sift

Uncertain

0.0040

D;D;D

Sift4G

Uncertain

0.0020

D;D;.

Polyphen

1.0

D;.;.

Vest4

0.79

MVP

0.74

MPC

0.25

ClinPred

0.18

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.94

gMVP

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over