NM_014874.4(MFN2):c.311G>T (p.Arg104Leu) AND Charcot-Marie-Tooth disease, type 2

Clinical significance:Pathogenic (Last evaluated: Mar 27, 2017)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000532246.1

Allele description [Variation Report for NM_014874.4(MFN2):c.311G>T (p.Arg104Leu)]

NM_014874.4(MFN2):c.311G>T (p.Arg104Leu)

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.311G>T (p.Arg104Leu)
HGVS:
  • NC_000001.11:g.11992690G>T
  • NG_007945.1:g.17510G>T
  • NM_001127660.2:c.311G>T
  • NM_014874.4:c.311G>TMANE SELECT
  • NP_001121132.1:p.Arg104Leu
  • NP_055689.1:p.Arg104Leu
  • NP_055689.1:p.Arg104Leu
  • LRG_255t1:c.311G>T
  • LRG_255:g.17510G>T
  • LRG_255p1:p.Arg104Leu
  • NC_000001.10:g.12052747G>T
  • NM_014874.3:c.311G>T
Protein change:
R104L
Links:
dbSNP: rs863224068
NCBI 1000 Genomes Browser:
rs863224068
Molecular consequence:
  • NM_001127660.2:c.311G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_014874.4:c.311G>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

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000657724Invitaecriteria provided, single submitter
Pathogenic
(Mar 27, 2017)
germlineclinical testing

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

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):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Invitae, SCV000657724.1

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

Description

This sequence change replaces arginine with leucine at codon 104 of the MFN2 protein (p.Arg104Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. It also falls at the last nucleotide of exon 4 of the MFN2 coding sequence. This variant is not present in population databases (ExAC no frequency). This variant has been reported in multiple individuals affected with Charcot-Marie-Tooth disease (PMID: 22492563). ClinVar contains an entry for this variant (Variation ID: 214651). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. A different missense substitution at this codon (p.Arg104Trp) has been determined to be pathogenic (PMID: 26307494, 18425620). This suggests that the arginine residue is critical for MFN2 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.

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

Last Updated: Dec 4, 2021

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