NM_002437.5(MPV17):c.122G>A (p.Arg41Gln) AND Charcot-Marie-Tooth disease, axonal, type 2EE

Germline classification:: Pathogenic/Likely pathogenic (7 submissions)
Last evaluated:: May 28, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000768421.18

Allele description [Variation Report for NM_002437.5(MPV17):c.122G>A (p.Arg41Gln)]

NM_002437.5(MPV17):c.122G>A (p.Arg41Gln)

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.122G>A (p.Arg41Gln)

HGVS:

NC_000002.12:g.27313058C>T
NG_008075.1:g.14507G>A
NG_033055.1:g.206G>A
NM_002437.5:c.122G>AMANE SELECT
NP_002428.1:p.Arg41Gln
NC_000002.11:g.27535925C>T
NM_002437.4:c.122G>A

Protein change:

R41Q; ARG41GLN

Links:

OMIM: 137960.0009; dbSNP: rs140992482

NCBI 1000 Genomes Browser:

rs140992482

Molecular consequence:

NM_002437.5:c.122G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Charcot-Marie-Tooth disease, axonal, type 2EE
Synonyms:: CHARCOT-MARIE-TOOTH NEUROPATHY, TYPE 2EE
Identifiers:: MONDO: MONDO:0032728; MedGen: C5193076; OMIM: 618400

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000899173	OMIM	no assertion criteria provided	Pathogenic (Apr 29, 2019)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 26437932, 30298599
SCV000998883	SIB Swiss Institute of Bioinformatics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Aug 13, 2019)	unknown	curation	PubMed (3) [See all records that cite these PMIDs] 26437932, 30298599, 25741868
SCV001524350	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 16, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001548316	CMT Laboratory, Bogazici University	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 1, 2020)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25741868, 31673878
SCV001760082	Genomics England Pilot Project, Genomics England	no assertion criteria provided (ACGS Guidelines, 2016)	Likely pathogenic	germline	clinical testing	Citation Link,
SCV003841957	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 23, 2023)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 23714749, 26437932, 25741868
SCV005090992	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 28, 2024)	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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	1	1	not provided	not provided	yes	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

MPV17 mutations in juvenile- and adult-onset axonal sensorimotor polyneuropathy.

Baumann M, Schreiber H, Schlotter-Weigel B, Löscher WN, Stucka R, Karall D, Strom TM, Bauer P, Krabichler B, Fauth C, Glaeser D, Senderek J.

Clin Genet. 2019 Jan;95(1):182-186. doi: 10.1111/cge.13462. Epub 2018 Oct 25.

PubMed [citation]

PMID:: 30298599

The first biallelic missense mutation in the FXN gene in a consanguineous Turkish family with Charcot-Marie-Tooth-like phenotype.

Candayan A, Yunisova G, Çakar A, Durmuş H, Başak AN, Parman Y, Battaloğlu E.

Neurogenetics. 2020 Jan;21(1):73-78. doi: 10.1007/s10048-019-00594-1. Epub 2019 Oct 31.

PubMed [citation]

PMID:: 31673878

See all PubMed Citations (5)

Details of each submission

From OMIM, SCV000899173.2

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

Description

In 2 unrelated Korean patients with autosomal recessive Charcot-Marie-Tooth neuropathy type 2EE (CMT2EE; 618400), Choi et al. (2015) identified a homozygous c.122G-A transition in the MPV17 gene, resulting in an arg41-to-gln (R41Q) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. The mutation was not found in the dbSNP (build 142) or 1000 Genomes Project databases, but was found at a low frequency in the Exome Sequencing Project (0.00008) and ExAC (0.00002471) databases. Transfection of the R41Q mutation into murine motor neurons inhibited cell proliferation, caused reduced of several OXPHOS proteins, and induced mtDNA depletion compared to controls.

Baumann et al. (2019) identified a homozygous R41Q mutation in the MPV17 gene in 2 Bosnian patients with CMT2EE. The mutation was found by Sanger sequencing and segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed.

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

From SIB Swiss Institute of Bioinformatics, SCV000998883.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (3)

Description

This variant is interpreted as a Likely pathogenic for Charcot-Marie-Tooth disease, axonal, 2EE, autosomal recessive. The following ACMG Tag(s) were applied: PM2, PP1, PS3-supporting, PM3.

#	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 Baylor Genetics, SCV001524350.2

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

#	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 CMT Laboratory, Bogazici University, SCV001548316.1

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

#	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		1	not provided	1	not provided

From Genomics England Pilot Project, Genomics England, SCV001760082.1

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

#	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

From 3billion, SCV003841957.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 26437932). In silico tool predictions suggest damaging effect of the variant on gene or gene product (3Cnet: 0.88). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000626263). A different missense change at the same codon (p.Arg41Trp) has been reported to be associated with MPV17 related disorder (ClinVar ID: VCV000214660 / PMID: 23714749). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

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

From Laboratory of Medical Genetics, National & Kapodistrian University of Athens, SCV005090992.1

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

Description

PS3, PM2, PM5, PP2, PP5- The variant has been reported in ClinVar as Pathogenic by other laboratories (Variation ID: 626263). Low frequency in gnomAD population databases. Functional studies support pathogenic effect (PMID: 26437932)

#	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: Nov 3, 2024

Relating variation to medicine