rs121909723

chr2-27313032-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PM5 PP5_Very_Strong

The NM_002437.5(MPV17):c.148C>T(p.Arg50Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000173 in 1,614,068 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R50Q) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: MPV17 NM_002437.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 2.14

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a chain Protein Mpv17 (size 175) in uniprot entity MPV17_HUMAN there are 36 pathogenic changes around while only 6 benign (86%) in NM_002437.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-27313031-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 16160.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant 2-27313032-G-A is Pathogenic according to our data. Variant chr2-27313032-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 16162.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-27313032-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MPV17	NM_002437.5	c.148C>T	p.Arg50Trp	missense_variant	3/8	ENST00000380044.6
MPV17	XM_005264326.5	c.148C>T	p.Arg50Trp	missense_variant	3/8
MPV17	XM_017004151.2	c.100C>T	p.Arg34Trp	missense_variant	3/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MPV17	ENST00000380044.6	c.148C>T	p.Arg50Trp	missense_variant	3/8	1	NM_002437.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251474 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135908

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: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000178 AC: 26 AN: 1461894 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000189

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152174 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74326

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000278 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 04, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 27, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 28, 2016	The R50W pathogenic variant in the MPV17 gene has been reported previously in multiple individuals with clinical features consistent with hepatocerebral mitochondrial DNA depletion syndrome in the homozygous state, as well as in the heterozygous state in the presence of a second MPV17 variant (Spinazzola et al., 2006; Wong et al., 2007; Vilarinho et al., 2014). Additionally, functional studies in yeast with the R50W variant show that this variant impacts the function of the protein (Spinazzola et al., 2006). The R50W variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R50W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R50W as a pathogenic variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 29, 2023	Experimental studies have shown that this missense change affects MPV17 function (PMID: 16582910). This variant disrupts the p.Arg50 amino acid residue in MPV17. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16582910, 16909392). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 16162). This missense change has been observed in individual(s) with clinical features of MPV17-related conditions (PMID: 16582910, 17694548, 25016221). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs121909723, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 50 of the MPV17 protein (p.Arg50Trp). -

Mitochondrial DNA depletion syndrome 6 (hepatocerebral type) Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	Yale Center for Mendelian Genomics, Yale University	Jul 10, 2014	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2006	- -

Mitochondrial DNA depletion syndrome 15 (hepatocerebral type) Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

May 20, 2021

- -

Charcot-Marie-Tooth disease, axonal, type 2EE Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 06, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Pathogenic	0.50
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.79	D
M_CAP	Pathogenic	0.78	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A
PROVEAN	Benign	1.4	N
REVEL	Uncertain	0.35
Sift	Benign	0.54	T
Vest4		0.52
MutPred		0.15		Loss of loop (P = 0.0288);
MVP		0.58
ClinPred		1.0	D
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs121909723; hg19: chr2-27535899; COSMIC: COSV51992038; COSMIC: COSV51992038;