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NM_014874.4(MFN2):c.776G>T (p.Arg259Leu) AND Charcot-Marie-Tooth disease type 2

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Dec 27, 2018
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV000796767.8

Allele description [Variation Report for NM_014874.4(MFN2):c.776G>T (p.Arg259Leu)]

NM_014874.4(MFN2):c.776G>T (p.Arg259Leu)

Gene:
MFN2:mitofusin 2 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
1p36.22
Genomic location:
Preferred name:
NM_014874.4(MFN2):c.776G>T (p.Arg259Leu)
HGVS:
  • NC_000001.11:g.11999055G>T
  • NG_007945.1:g.23875G>T
  • NM_001127660.2:c.776G>T
  • NM_014874.4:c.776G>TMANE SELECT
  • NP_001121132.1:p.Arg259Leu
  • NP_055689.1:p.Arg259Leu
  • NP_055689.1:p.Arg259Leu
  • LRG_255t1:c.776G>T
  • LRG_255:g.23875G>T
  • LRG_255p1:p.Arg259Leu
  • NC_000001.10:g.12059112G>T
  • NM_014874.3:c.776G>T
Protein change:
R259L
Links:
dbSNP: rs755065651
NCBI 1000 Genomes Browser:
rs755065651
Molecular consequence:
  • NM_001127660.2:c.776G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_014874.4:c.776G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Charcot-Marie-Tooth disease type 2
Synonyms:
Charcot-Marie-Tooth, Type 2
Identifiers:
MONDO: MONDO:0018993; MedGen: C0270914

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000936294Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Dec 27, 2018) 		germlineclinical testing

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000936294.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

This sequence change replaces arginine with leucine at codon 259 of the MFN2 protein (p.Arg259Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg259 amino acid residue in MFN2. Other variant(s) that disrupt this residue have been observed in individuals with MFN2-related conditions (PMID: 25957633, 24450158, 22492563, 24863639, 24627108), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed to be de novo in an individual affected with Charcot-Marie-Tooth disease (PMID: 19350291). This variant is not present in population databases (ExAC no frequency).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024