rs139076647

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM5PP3PP5

The ENST00000341695.10(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 Conflicting classifications of pathogenicity (no stars). 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
ENST00000341695.10 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7U:1

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 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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 id is 1189243.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

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 [Conflicting_classifications_of_pathogenicity]. Clinvar id is 372225.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Pathogenic=3, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PPA2	NM_176869.3 linkuse as main transcript	c.380G>T	p.Arg127Leu	missense_variant	5/12	ENST00000341695.10	NP_789845.1
PPA2	NM_006903.4 linkuse as main transcript	c.380G>T	p.Arg127Leu	missense_variant	5/11		NP_008834.3
PPA2	NM_176866.2 linkuse as main transcript	c.222+10237G>T		intron_variant			NP_789842.2
PPA2	NM_176867.3 linkuse as main transcript	c.157+27450G>T		intron_variant			NP_789843.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPA2	ENST00000341695.10 linkuse as main transcript	c.380G>T	p.Arg127Leu	missense_variant	5/12	1	NM_176869.3	ENSP00000343885	P1	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

GnomAD3 exomes

AF:

0.000151

AC:

AN:

244404

Hom.:

AF XY:

0.000159

AC XY:

AN XY:

132410

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 SAS 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

Gnomad4 AFR exome

AF:

0.0000302

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000188

Gnomad4 NFE exome

AF:

0.000580

Gnomad4 OTH exome

AF:

0.000799

GnomAD4 genome

AF:

0.000210

AC:

AN:

152250

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000397

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000372

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: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Sudden cardiac failure, infantile

Pathogenic:4

Likely pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 23, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jun 24, 2022	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 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Royal Brompton Clinical Genetics And Genomics Laboratory, NHS South East Genomic Laboratory Hub	Sep 14, 2017	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

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 13, 2024	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 19, 2024	PP1_strong, PM3_very_strong, PS3_supporting, PS4_moderate -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 08, 2024	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; Invitae). 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). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PPA2 protein function. For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 15, 2021

(Kennedy, 2016; Phoon, 2020) Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

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;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D

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

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

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