rs139076647

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM5PP3PP5_Very_Strong

The NM_176869.3(PPA2):c.380G>T(p.Arg127Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000457 in 1,605,628 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R127C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00048 ( 0 hom. )

Consequence

PPA2
NM_176869.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 7.81

Publications

9 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: Pathogenic. The variant received 11 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr4-105446445-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1189243.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.808

PP5

Variant 4-105446444-C-A is Pathogenic according to our data. Variant chr4-105446444-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 372225.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.380G>T	p.Arg127Leu	missense_variant	Exon 5 of 12	ENST00000341695.10	NP_789845.1	Q9H2U2-1
PPA2	NM_006903.4 link	c.380G>T	p.Arg127Leu	missense_variant	Exon 5 of 11		NP_008834.3	Q9H2U2-3
PPA2	NM_176866.2 link	c.222+10237G>T		intron_variant	Intron 2 of 7		NP_789842.2	Q9H2U2-6
PPA2	NM_176867.3 link	c.157+27450G>T		intron_variant	Intron 1 of 5		NP_789843.2	Q9H2U2-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPA2	ENST00000341695.10 link	c.380G>T	p.Arg127Leu	missense_variant	Exon 5 of 12	1	NM_176869.3	ENSP00000343885.5		Q9H2U2-1

Frequencies

GnomAD3 genomes

AF:

0.000210

AC:

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000397

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000151

AC:

AN:

244404

AF XY:

0.000159

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000186

Gnomad NFE exome

AF:

0.000296

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000483

AC:

702

AN:

1453378

Hom.:

Cov.:

AF XY:

0.000476

AC XY:

344

AN XY:

722764

show subpopulations

African (AFR)

AF:

0.0000302

AC:

AN:

33080

American (AMR)

AF:

0.00

AC:

AN:

43268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26006

East Asian (EAS)

AF:

0.00

AC:

AN:

39082

South Asian (SAS)

AF:

0.00

AC:

AN:

84048

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

53206

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.000580

AC:

643

AN:

1108862

Other (OTH)

AF:

0.000799

AC:

AN:

60072

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

102

136

170

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

<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:

0.000210

AC:

AN:

152250

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41564

American (AMR)

AF:

0.00

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000397

AC:

AN:

67978

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

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:

0.000348

Hom.:

Bravo

AF:

0.000196

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000165

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Sudden cardiac failure, infantile

Pathogenic:4

Genomics England Pilot Project, Genomics England

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 23, 2016

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Jun 24, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: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 Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with infantile sudden cardiac failure (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 arginine to leucine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 44 heterozygotes, 0 homozygotes). (SP) 0309 - Two alternative amino acid changes at the same position have been observed in gnomAD (highest allele count in: v2, 12 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated pyrophosphatase domain (PDB). (I) 0708 - Other missense variants comparable to the one identified in this case have conflicting previous evidence for pathogenicity. p.(Arg127Cys) has been reported as compound heterozygous in a child with epilepsy and recurrent acute cardiac failure (PMID: 33826954), and is listed in ClinVar as a VUS. p.(Arg127His) has been reported as a VUS in ClinVar. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in five unrelated families with children suffering sudden cardiac failure during early childhood or alcohol-induced sudden cardiac arrest during their teens, and in one asymptomatic 10-year old child (PMIDs: 27523597, 31705601, 34400813). It has also been reported as likely pathogenic by multiple clinical testing laboratories (ClinVar). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Enzyme activity in the recombinant PPA2 protein harbouring R127L was significantly decreased compared to a wild-type control (PMID: 34400813). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Sep 14, 2017

Royal Brompton Clinical Genetics And Genomics Laboratory, NHS South East Genomic Laboratory Hub

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.380G>T variant is present in 48/270550 individuals in the gnomAD control population in heterozygous form, and has previously been reported in compound heterozygosity with another likely pathogenic PPA2 variant in a single infant with sudden infantile cardiac failure (Kennedy et al (2016) Am J Hum Genet 99(3):674-682). This variant was inherited from a heterozygous carrier parent. In silico analysis predicts a pathogenic effect on protein function, and the affected amino acid is highly conserved. In view of the evidence, we have interpreted this variant as likely to be pathogenic when inherited with another (likely) pathogenic variant. The c.380G>T variant is also likely to be benign when carried in isolation. -

not provided

Pathogenic:3

May 13, 2024

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate that this variant has a damaging effect on mitochondrial pyrophosphatase enzyme activity (PMID: 34400813); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; A different missense change at this residue (p.(R127C)) has been reported in association with an autosomal recessive PPA2-related disorder (PMID: 33826954); This variant is associated with the following publications: (PMID: 34758253, 31705601, 27523597, 34930847, Genthe_2023[case report], 37249496, 34400813, 33826954) -

Jul 19, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP1_strong, PM3_very_strong, PS3_supporting, PS4_moderate -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 127 of the PPA2 protein (p.Arg127Leu). This variant is present in population databases (rs139076647, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of sudden cardiac failure (PMID: 27523597; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 372225). 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%. For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases

Pathogenic:1

May 07, 2025

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.380G>T (p.R127L) alteration is located in exon 5 (coding exon 5) of the PPA2 gene. This alteration results from a G to T substitution at nucleotide position 380, causing the arginine (R) at amino acid position 127 to be replaced by a leucine (L). This variant has been identified in the homozygous state and/or in conjunction with other variant(s) in this same gene in individual(s) with features consistent with PPA2-related early sudden cardiac failure and segregated with disease in at least one family (Kennedy, 2016; Phoon, 2020; Guimier, 2021). This amino acid position is highly conserved in available vertebrate species. Based on internal structural analysis, this variant is anticipated to disrupt a region of known function (Bezpalaya, 2025). In an assay testing PPA2 function, this variant showed a functionally abnormal result (Guimier, 2021). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Sudden cardiac failure, alcohol-induced;C4310664:Sudden cardiac failure, infantile

Pathogenic:1

Jun 14, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Uncertain

0.093

BayesDel_noAF

Pathogenic

0.23

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.42

T;.;T;.

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

D;D;D;D

M_CAP

Benign

0.042

MetaRNN

Pathogenic

0.81

D;D;D;D

MetaSVM

Benign

-0.29

MutationAssessor

Pathogenic

3.6

H;H;.;.

PhyloP100

7.8

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-6.6

D;D;D;D

REVEL

Uncertain

0.64

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;.;D

Polyphen

0.99

D;D;.;.

Vest4

0.99

MVP

0.63

MPC

0.55

ClinPred

0.93

GERP RS

5.1

Varity_R

0.92

gMVP

0.97

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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