rs146013446

chr4-105437964-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 12P and 1B. PM1 PM2 PP5_Very_Strong BP4

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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15
• Conservation: PhyloP100: 7.81

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_176869.3
• 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	UniProt
PPA2	NM_176869.3	c.514G>A	p.Glu172Lys	missense_variant	6/12	ENST00000341695.10
PPA2	NM_006903.4	c.441+8419G>A		intron_variant
PPA2	NM_176866.2	c.223-13642G>A		intron_variant
PPA2	NM_176867.3	c.157+35930G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPA2	ENST00000341695.10	c.514G>A	p.Glu172Lys	missense_variant	6/12	1	NM_176869.3	P1

Frequencies

GnomAD3 genomes AF: 0.000677 AC: 103 AN: 152130 Hom.: 0 Cov.: 32

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.: 0 AF XY: 0.000517 AC XY: 68 AN XY: 131620

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.: 0 Cov.: 30 AF XY: 0.00103 AC XY: 743 AN XY: 723000

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.: 0 Cov.: 32 AF XY: 0.000672 AC XY: 50 AN XY: 74442

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.: 0

Bravo AF: 0.000540

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000486 AC: 59

EpiCase AF: 0.000711

EpiControl AF: 0.000775

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Sudden cardiac failure, infantile Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Nov 16, 2017	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 25, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 23, 2016	- -
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. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 06, 2021	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, 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 glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2) (147 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) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has previously been reported in at least 5 unrelated families with PPA2-related mitochondrial cardiomyopathy and sudden cardiac death (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) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
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. -
Likely pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Oct 04, 2019	ACMG codes: PS4M, PM2, PM3 -

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 12, 2023	Published functional studies demonstrate this variant results in decreased enzyme activity (Guimier et al., 2016; Kennedy et al., 2016); 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, 27523597, 30384889, 34400813) -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 01, 2022	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	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. -

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	T
BayesDel_noAF	Uncertain	0.040
Cadd	Pathogenic	32
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	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.25	T;T;T
MetaSVM	Uncertain	-0.013	T
MutationAssessor	Pathogenic	3.5	M;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.62	T
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	T
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

Other links and lift over

dbSNP: rs146013446; hg19: chr4-106359121; COSMIC: COSV58993447; COSMIC: COSV58993447;