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NM_014874.4(MFN2):c.1082A>C (p.His361Pro) AND Charcot-Marie-Tooth disease type 2

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Nov 12, 2021
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:
RCV000653938.5

Allele description [Variation Report for NM_014874.4(MFN2):c.1082A>C (p.His361Pro)]

NM_014874.4(MFN2):c.1082A>C (p.His361Pro)

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.1082A>C (p.His361Pro)
HGVS:
  • NC_000001.11:g.12002025A>C
  • NG_007945.1:g.26845A>C
  • NM_001127660.2:c.1082A>C
  • NM_014874.4:c.1082A>CMANE SELECT
  • NP_001121132.1:p.His361Pro
  • NP_055689.1:p.His361Pro
  • NP_055689.1:p.His361Pro
  • LRG_255t1:c.1082A>C
  • LRG_255:g.26845A>C
  • LRG_255p1:p.His361Pro
  • NC_000001.10:g.12062082A>C
  • NM_014874.3:c.1082A>C
Protein change:
H361P
Links:
dbSNP: rs1064793170
NCBI 1000 Genomes Browser:
rs1064793170
Molecular consequence:
  • NM_001127660.2:c.1082A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_014874.4:c.1082A>C - 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
SCV000775828Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Nov 12, 2021) 		germlineclinical testing

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

Help

Summary from all submissions

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

Citations

PubMed

Axonal neuropathy with optic atrophy is caused by mutations in mitofusin 2.

Züchner S, De Jonghe P, Jordanova A, Claeys KG, Guergueltcheva V, Cherninkova S, Hamilton SR, Van Stavern G, Krajewski KM, Stajich J, Tournev I, Verhoeven K, Langerhorst CT, de Visser M, Baas F, Bird T, Timmerman V, Shy M, Vance JM.

Ann Neurol. 2006 Feb;59(2):276-81.

PubMed [citation]
PMID:
16437557

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 Invitae, SCV000775828.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

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 MFN2 protein function. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.His361 amino acid residue in MFN2. Other variant(s) that disrupt this residue have been observed in individuals with MFN2-related conditions (PMID: 16437557), which suggests that this may be a clinically significant amino acid residue. ClinVar contains an entry for this variant (Variation ID: 543232). This missense change has been observed in individual(s) with clinical features of autosomal dominant MFN2-related conditions (Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 361 of the MFN2 protein (p.His361Pro).

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

Last Updated: Feb 14, 2024