NM_002437.5(MPV17):c.107A>C (p.Gln36Pro) AND Mitochondrial DNA depletion syndrome 6 (hepatocerebral type)

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Aug 13, 2019
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000855707.5

Allele description [Variation Report for NM_002437.5(MPV17):c.107A>C (p.Gln36Pro)]

NM_002437.5(MPV17):c.107A>C (p.Gln36Pro)

Gene:

MPV17:mitochondrial inner membrane protein MPV17 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2p23.3

Genomic location:

Preferred name:

NM_002437.5(MPV17):c.107A>C (p.Gln36Pro)

HGVS:

NC_000002.12:g.27313073T>G
NG_008075.1:g.14492A>C
NG_033055.1:g.191A>C
NM_002437.5:c.107A>CMANE SELECT
NP_002428.1:p.Gln36Pro
NC_000002.11:g.27535940T>G

Protein change:

Q36P

Links:

dbSNP: rs762327729

NCBI 1000 Genomes Browser:

rs762327729

Molecular consequence:

NM_002437.5:c.107A>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Mitochondrial DNA depletion syndrome 6 (hepatocerebral type)
Synonyms:: Navajo neurohepatopathy; Navajo neuropathy; Mitochondrial DNA depletion syndrome type 6
Identifiers:: MONDO: MONDO:0009747; MedGen: C1850406; Orphanet: 255229; OMIM: 256810

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000998881	SIB Swiss Institute of Bioinformatics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Aug 13, 2019)	unknown	curation	PubMed (2) [See all records that cite these PMIDs] 23714749, 25741868
SCV004101547	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000998881

SIB Swiss Institute of Bioinformatics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Aug 13, 2019)

unknown

curation

PubMed (2)
[See all records that cite these PMIDs]

SCV004101547

Neuberg Centre For Genomic Medicine, NCGM

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	curation
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Clinical, biochemical, cellular and molecular characterization of mitochondrial DNA depletion syndrome due to novel mutations in the MPV17 gene.

Uusimaa J, Evans J, Smith C, Butterworth A, Craig K, Ashley N, Liao C, Carver J, Diot A, Macleod L, Hargreaves I, Al-Hussaini A, Faqeih E, Asery A, Al Balwi M, Eyaid W, Al-Sunaid A, Kelly D, van Mourik I, Ball S, Jarvis J, Mulay A, et al.

Eur J Hum Genet. 2014 Feb;22(2):184-91. doi: 10.1038/ejhg.2013.112. Epub 2013 May 29.

PubMed [citation]

PMID:: 23714749
PMCID:: PMC3895632

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From SIB Swiss Institute of Bioinformatics, SCV000998881.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (2)

Description

This variant is interpreted as a variant of uncertain significance for Mitochondrial DNA depletion syndrome 6, autosomal recessive. The following ACMG Tag(s) were applied: PM2, PM3-supporting.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Neuberg Centre For Genomic Medicine, NCGM, SCV004101547.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

The c.107A>C (p.Gln36Pro) missense variant in MPV17 gene has been reported in multiple patients affected with Mitochondrial DNA (mtDNA) depletion syndromes (Uusimaa et al., 2014). This variant is reported with the allele frequency (0.0003%) in the gnomAD and novel in 1000 genome database. This variant has been reported to the ClinVar database as Variant of Uncertain Significance. The amino acid Gln at position 36 is changed to a Pro changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Gln36Pro in MPV17 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. The above variant was also detected in the spouse.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Apr 6, 2024

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