rs267607258

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_002437.5(MPV17):c.293C>T(p.Pro98Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000651 in 1,613,968 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 Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000064 ( 0 hom. )

Consequence

MPV17
NM_002437.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:15O:1

Conservation

PhyloP100: 5.45

Variant links:

Genes affected

MPV17 (HGNC:7224): (mitochondrial inner membrane protein MPV17) This gene encodes a mitochondrial inner membrane protein that is implicated in the metabolism of reactive oxygen species. Mutations in this gene have been associated with the hepatocerebral form of mitochondrial DNA depletion syndrome (MDDS). [provided by RefSeq, Jul 2008]

MPV17 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a chain Protein Mpv17 (size 175) in uniprot entity MPV17_HUMAN there are 13 pathogenic changes around while only 1 benign (93%) in NM_002437.5

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.966

PP5

Variant 2-27312576-G-A is Pathogenic according to our data. Variant chr2-27312576-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 38355.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MPV17	NM_002437.5 link	c.293C>T	p.Pro98Leu	missense_variant	5/8	ENST00000380044.6	NP_002428.1	P39210A0A0S2Z3Z9
MPV17	XM_005264326.5 link	c.293C>T	p.Pro98Leu	missense_variant	5/8		XP_005264383.1	P39210A0A0S2Z3Z9
MPV17	XM_017004151.2 link	c.245C>T	p.Pro82Leu	missense_variant	5/8		XP_016859640.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MPV17	ENST00000380044.6 link	c.293C>T	p.Pro98Leu	missense_variant	5/8	1	NM_002437.5	ENSP00000369383.1		P39210

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000827

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000557

AC:

AN:

251314

Hom.:

AF XY:

0.0000663

AC XY:

AN XY:

135824

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000616

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000636

AC:

AN:

1461784

Hom.:

Cov.:

AF XY:

0.0000509

AC XY:

AN XY:

727184

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.000162

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000639

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000789

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000827

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000383

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mitochondrial DNA depletion syndrome 6 (hepatocerebral type)

Pathogenic:5Other:1

Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Apr 22, 2022	- -
Pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Aug 13, 2019	This variant is interpreted as a Pathogenic for Mitochondrial DNA depletion syndrome 6, autosomal recessive. The following ACMG Tag(s) were applied: PM2, PP3, PS3-Moderate, PM3-Very Strong. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Oct 05, 2021	PM1, PM2, PP3, PP5 -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	-	- -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 98 of the MPV17 protein (p.Pro98Leu). This variant is present in population databases (rs267607258, gnomAD 0.02%). This missense change has been observed in individual(s) with mitochondrial DNA depletion syndrome (PMID: 20074988, 22508010, 23714749, 25129007, 27536553). 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: 38355). 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 MPV17 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MPV17 function (PMID: 25861990). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 20, 2023	Published functional studies demonstrate a damaging effect as P98L results in a MPV17-channel that was prone to closing under reducing conditions and did not close completely compared to the wild-type channel (Antonenkov et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 24190800, 22508010, 20074988, 23714749, 27536553, 27896091, 28776642, 32703289, 33083013, 34023347, 35314707, 34979697, 34052969, 25861990, 24077912) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 19, 2018	- -

Charcot-Marie-Tooth disease, axonal, type 2EE

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 14, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 29, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	- -

MPV17-related disorder

Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Mar 28, 2024	The MPV17 c.293C>T variant is predicted to result in the amino acid substitution p.Pro98Leu. This variant has been reported in the homozygous and compound heterozygous states in individuals with mitochondrial DNA depletion syndrome (Blakely et al. 2012. PubMed ID: 22508010; Bijarnia-Mahay et al. 2014. PubMed ID: 25129007; Uusimaa et al. 2014. PubMed ID: 23714749; Kim et al. 2016. PubMed ID: 27536553; El-Hattab et al. 2010. PubMed ID: 20074988). This variant is reported in 0.016% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The MPV17 c.293C>T (p.Pro98Leu) variant has been reported in at least eight studies in which it is found in a total of ten individuals with mitochondrial DNA depletion-related syndromes, including four in a homozygous state (two of whom were siblings) and six in a compound heterozygous state (El-Hattab et al. 2010; Blakely et al. 2012; Uusimaa et al. 2014; Mendelsohn et al. 2014; Bijarnia-Mahay et al. 2014; Harvengt et al. 2014; Kim et al. 2016; Khoda et al. 2016). Mitochondrial DNA was shown to be decreased by 20% in hepatic tissue in one of the compound heterozygous individuals (Khoda et al. 2016). The variant has also been detected in a heterozygous state in four unaffected relatives of probands. Control data are unavailable for this variant which is reported at a frequency of 0.00006 in the European (non-Finnish) population of the Exome Aggregation Consortium. The MPV17 protein functions as a non-selective channel modulating the membrane potential to preserve mitochondrial homeostasis, and functional studies demonstrated that the p.Pro98Leu variant impacts the ability of the channel to close tightly (Antonenkov et al. 2015). Based on the evidence, the p.Pro98Leu variant is classified as pathogenic for MPV17-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Mitochondrial DNA depletion syndrome 6 (hepatocerebral type);C5193076:Charcot-Marie-Tooth disease, axonal, type 2EE

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 08, 2024

- -

Mitochondrial DNA depletion syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Nov 10, 2023

Variant summary: MPV17 c.293C>T (p.Pro98Leu) 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 5.6e-05 in 251314 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MPV17 causing Mitochondrial DNA Depletion Syndrome - MPV17 Related (5.6e-05 vs 0.0011), allowing no conclusion about variant significance. c.293C>T has been reported in the literature in multiple individuals affected with Mitochondrial DNA Depletion Syndrome - MPV17 Related (e.g. Blakely_2015, El-Hattab_2010, Uusimaa_2014, Mundlamuri_2021). 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,that this variant may affect gating properties of the channel (Antonenkov_2015). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. The following publications have been ascertained in the context of this evaluation (PMID: 25861990, 22508010, 20074988, 34979697, 23714749). All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.83

D;.;D;D;D;D;.

Eigen

Pathogenic

0.77

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.92

.;D;D;D;D;D;D

M_CAP

Pathogenic

0.78

MetaRNN

Pathogenic

0.97

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.1

H;.;H;.;.;.;.

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-9.5

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

REVEL

Pathogenic

0.91

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

D;D;D;D;D;D;.

Polyphen

1.0

D;D;D;.;.;.;.

Vest4

0.79

MVP

0.93

MPC

1.0

ClinPred

1.0

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.80

gMVP

0.86

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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