rs138215926

Positions:

• chr4-105399137-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 9.48

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-105399137-G-A is Pathogenic according to our data. Variant chr4-105399137-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 372226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-105399137-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPA2	ENST00000341695.10	c.683C>T	p.Pro228Leu	missense_variant	8/12	1	NM_176869.3	ENSP00000343885.5

Frequencies

GnomAD3 genomes AF: 0.000434 AC: 66 AN: 152018 Hom.: 0 Cov.: 32

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

GnomAD3 exomes AF: 0.000202 AC: 49 AN: 242474 Hom.: 0 AF XY: 0.000206 AC XY: 27 AN XY: 131216

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 SAS 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.: 0 Cov.: 30 AF XY: 0.000328 AC XY: 237 AN XY: 722198

Gnomad4 AFR exome AF: 0.000122

Gnomad4 AMR exome AF: 0.000416

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000120

Gnomad4 FIN exome AF: 0.0000383

Gnomad4 NFE exome AF: 0.000407

Gnomad4 OTH exome AF: 0.000233

GnomAD4 genome AF: 0.000434 AC: 66 AN: 152136 Hom.: 0 Cov.: 32 AF XY: 0.000403 AC XY: 30 AN XY: 74380

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.00164

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000945

Gnomad4 NFE AF: 0.000471

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000360 Hom.: 0

Bravo AF: 0.000623

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000247 AC: 30

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:6

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 21, 2021	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 15, 2024	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) -
Likely pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	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). 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). For these reasons, this variant has been classified as Pathogenic. -

Sudden cardiac failure, infantile Pathogenic:2

Likely 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 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 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 21, 2022	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 does not allow conclusions about variant significance. c.683C>T has been reported in the literature as a compound heterozygous genotype in at-least 4 affected individuals from a single family affected with Sudden Cardiac Failure, Infantile (example, Kennedy_2016 cited in Phoon_2020). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Kennedy_2016). The most pronounced variant effect results in 24-28% of normal Pyrophosphatase activity in-vitro. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely 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

Apr 04, 2022

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	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T;.;.;.;T
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D
M_CAP	Uncertain	0.098	D
MetaRNN	Uncertain	0.42	T;T;T;T;T
MetaSVM	Uncertain	0.66	D
MutationAssessor	Pathogenic	4.3	H;.;.;.;.
PrimateAI	Uncertain	0.56	T
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	D
GERP RS		5.9
Varity_R		0.97
gMVP		0.82

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

Other links and lift over

dbSNP: rs138215926; hg19: chr4-106320294; COSMIC: COSV58994362; COSMIC: COSV58994362;