NM_014874.4(MFN2):c.1136T>C (p.Leu379Pro) AND Charcot-Marie-Tooth disease type 2

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Nov 3, 2023
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:: RCV003766729.2

Allele description [Variation Report for NM_014874.4(MFN2):c.1136T>C (p.Leu379Pro)]

NM_014874.4(MFN2):c.1136T>C (p.Leu379Pro)

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.1136T>C (p.Leu379Pro)

HGVS:

NC_000001.11:g.12002079T>C
NG_007945.1:g.26899T>C
NM_001127660.2:c.1136T>C
NM_014874.4:c.1136T>CMANE SELECT
NP_001121132.1:p.Leu379Pro
NP_055689.1:p.Leu379Pro
LRG_255:g.26899T>C
NC_000001.10:g.12062136T>C

Protein change:

L379P

Links:

dbSNP: rs1064797107

NCBI 1000 Genomes Browser:

rs1064797107

Molecular consequence:

NM_001127660.2:c.1136T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_014874.4:c.1136T>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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004672994	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Nov 3, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 33415332, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004672994

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Nov 3, 2023)

germline

clinical testing

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

Help

Summary from all submissions

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

Citations

PubMed

Natural history of Charcot-Marie-Tooth disease type 2A: a large international multicentre study.

Pipis M, Feely SME, Polke JM, Skorupinska M, Perez L, Shy RR, Laura M, Morrow JM, Moroni I, Pisciotta C, Taroni F, Vujovic D, Lloyd TE, Acsadi G, Yum SW, Lewis RA, Finkel RS, Herrmann DN, Day JW, Li J, Saporta M, Sadjadi R, et al.

Brain. 2020 Dec 1;143(12):3589-3602. doi: 10.1093/brain/awaa323.

PubMed [citation]

PMID:: 33415332
PMCID:: PMC7805791

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, SCV004672994.1

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

Description

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 379 of the MFN2 protein (p.Leu379Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease type 2A (PMID: 33415332). ClinVar contains an entry for this variant (Variation ID: 424889). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MFN2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

Last Updated: Oct 20, 2024

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