rs138215926

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PP5_Very_Strong

The NM_176869.3(PPA2):c.683C>T(p.Pro228Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000347 in 1,604,770 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00043 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00034 ( 0 hom. )

Consequence

PPA2
NM_176869.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 9.48

Publications

14 publications found

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 Gene-Disease associations (from GenCC):

sudden cardiac failure, infantile
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine

PPA2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PP5

Variant 4-105399137-G-A is Pathogenic according to our data. Variant chr4-105399137-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 372226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPA2	NM_176869.3 link	c.683C>T	p.Pro228Leu	missense_variant	Exon 8 of 12	ENST00000341695.10	NP_789845.1	Q9H2U2-1
PPA2	NM_006903.4 link	c.596C>T	p.Pro199Leu	missense_variant	Exon 7 of 11		NP_008834.3	Q9H2U2-3
PPA2	NM_176866.2 link	c.377C>T	p.Pro126Leu	missense_variant	Exon 4 of 8		NP_789842.2	Q9H2U2-6
PPA2	NM_176867.3 link	c.185C>T	p.Pro62Leu	missense_variant	Exon 2 of 6		NP_789843.2	Q9H2U2-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPA2	ENST00000341695.10 link	c.683C>T	p.Pro228Leu	missense_variant	Exon 8 of 12	1	NM_176869.3	ENSP00000343885.5		Q9H2U2-1

Frequencies

GnomAD3 genomes

AF:

0.000434

AC:

AN:

152018

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00164

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000945

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000471

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000202

AC:

AN:

242474

AF XY:

0.000206

show subpopulations

Gnomad AFR exome

AF:

0.000127

Gnomad AMR exome

AF:

0.000217

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000484

Gnomad NFE exome

AF:

0.000332

Gnomad OTH exome

AF:

0.000338

GnomAD4 exome

AF:

0.000338

AC:

491

AN:

1452634

Hom.:

Cov.:

AF XY:

0.000328

AC XY:

237

AN XY:

722198

show subpopulations

African (AFR)

AF:

0.000122

AC:

AN:

32908

American (AMR)

AF:

0.000416

AC:

AN:

43272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25996

East Asian (EAS)

AF:

0.00

AC:

AN:

39534

South Asian (SAS)

AF:

0.0000120

AC:

AN:

83632

European-Finnish (FIN)

AF:

0.0000383

AC:

AN:

52246

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5738

European-Non Finnish (NFE)

AF:

0.000407

AC:

452

AN:

1109232

Other (OTH)

AF:

0.000233

AC:

AN:

60076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.436

Heterozygous variant carriers

101

126

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000434

AC:

AN:

152136

Hom.:

Cov.:

AF XY:

0.000403

AC XY:

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.000193

AC:

AN:

41524

American (AMR)

AF:

0.00164

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4806

European-Finnish (FIN)

AF:

0.0000945

AC:

AN:

10584

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000471

AC:

AN:

67986

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.520

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000346

Hom.:

Bravo

AF:

0.000623

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000247

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:6

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 21, 2021

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 228 of the PPA2 protein (p.Pro228Leu). This variant is present in population databases (rs138215926, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of PPA2-related conditions (PMID: 27523597). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 372226). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PPA2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PPA2 function (PMID: 27523597). For these reasons, this variant has been classified as Pathogenic. -

Clinical Genetics, Academic Medical Center

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 28, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate this variant has moderately reduced residual enzyme activity (PMID: 27523597); 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: 31705601, 27523597, 37249496, 37269378, 37869221, 34400813, 38582264, 30384889, Harris2024[preproof], 38893676) -

Sudden cardiac failure, infantile

Pathogenic:2

May 06, 2021

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as likely 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 proline to leucine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3) (66 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) 0803 - This variant has limited previous evidence of pathogenicity in one family with four affected offspring with PPA2-related mitochondrial cardiomyopathy and sudden cardiac death. (PMID: 27523597). (SP) 0902 - This variant has moderate evidence for segregation with disease in a single family (PMID: 27523597). (SP) 1002 - This variant has moderate 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 24%-28% decrease of residual activity of inorganic pyrophosphate substrate compared to wild-type. (PMID: 27523597) (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Apr 01, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: PPA2 c.683C>T (p.Pro228Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 242474 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in PPA2 causing Sudden Cardiac Failure, Infantile, allowing no conclusion about variant significance. c.683C>T has been reported in the presumed and confirmed compound heterozygous state in the literature in multiple individuals affected with clinical features of PPA2-related conditions (example, Kennedy_2016, Phoon_2020, Graham_2023, Gomez-Gonzalez_2024). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal activity (example, Kennedy_2016). The following publications have been ascertained in the context of this evaluation (PMID: 27523597, 31705601, 30384889, 37249496, 38582264). ClinVar contains an entry for this variant (Variation ID: 372226). Based on the evidence outlined above, the variant was classified as pathogenic. -

Sudden cardiac failure, alcohol-induced

Pathogenic:1

Nov 23, 2016

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Inborn genetic diseases

Pathogenic:1

Apr 04, 2022

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.683C>T (p.P228L) alteration is located in exon 8 (coding exon 8) of the PPA2 gene. This alteration results from a C to T substitution at nucleotide position 683, causing the proline (P) at amino acid position 228 to be replaced by a leucine (L). Based on data from gnomAD, the T allele has an overall frequency of 0.02% (58/273840) total alleles studied. The highest observed frequency was 0.03% (43/126958) of European (non-Finnish) alleles. This alteration was identified compound heterozygous with a second PPA2 variant and segregated with disease in several families in which affected individuals presented with acute heart failure or sudden cardiac death (Guimier, 2021; Kennedy, 2016). This amino acid position is highly conserved in available vertebrate species. E. coli strains expressing recombinant protein with the p.P228L variant showed 24-28% residual pyrophosphatase activity compared to wild type protein (Kennedy, 2016). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Uncertain

0.088

BayesDel_noAF

Pathogenic

0.20

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.45

T;.;.;.;T

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D;D;D;D

M_CAP

Uncertain

0.098

MetaRNN

Uncertain

0.42

T;T;T;T;T

MetaSVM

Uncertain

0.66

MutationAssessor

Pathogenic

4.3

H;.;.;.;.

PhyloP100

9.5

PrimateAI

Uncertain

0.56

PROVEAN

Pathogenic

-9.6

D;D;D;D;D

REVEL

Uncertain

0.55

Sift

Pathogenic

0.0

D;D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D;D

Polyphen

1.0

D;D;D;.;.

Vest4

0.84

MVP

0.89

MPC

0.49

ClinPred

1.0

GERP RS

5.9

Varity_R

0.97

gMVP

0.82

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over