NM_014874.4(MFN2):c.2146G>A (p.Ala716Thr) AND Charcot-Marie-Tooth disease, type 2

Clinical significance:Conflicting interpretations of pathogenicity, Likely benign(1);Uncertain significance(1) (Last evaluated: Sep 24, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000554698.7

Allele description [Variation Report for NM_014874.4(MFN2):c.2146G>A (p.Ala716Thr)]

NM_014874.4(MFN2):c.2146G>A (p.Ala716Thr)

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.2146G>A (p.Ala716Thr)
Other names:
p.A716T:GCC>ACC
HGVS:
  • NC_000001.11:g.12009668G>A
  • NG_007945.1:g.34488G>A
  • NM_001127660.2:c.2146G>A
  • NM_014874.3:c.2146G>A
  • NM_014874.4:c.2146G>AMANE SELECT
  • NP_001121132.1:p.Ala716Thr
  • NP_055689.1:p.Ala716Thr
  • NP_055689.1:p.Ala716Thr
  • LRG_255t1:c.2146G>A
  • LRG_255:g.34488G>A
  • LRG_255p1:p.Ala716Thr
  • NC_000001.10:g.12069725G>A
Protein change:
A716T
Links:
dbSNP: rs144860227
NCBI 1000 Genomes Browser:
rs144860227
Molecular consequence:
  • NM_001127660.2:c.2146G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_014874.3:c.2146G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_014874.4:c.2146G>A - 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
SCV000348007Illumina Clinical Services Laboratory,Illuminacriteria provided, single submitter
Likely benign
(Apr 27, 2017)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link,

SCV000657720Invitaecriteria provided, single submitter
Uncertain significance
(Sep 24, 2020)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Summary from all submissions

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

Citations

PubMed

Genetic epidemiology of Charcot-Marie-Tooth in the general population.

Braathen GJ, Sand JC, Lobato A, Høyer H, Russell MB.

Eur J Neurol. 2011 Jan;18(1):39-48. doi: 10.1111/j.1468-1331.2010.03037.x.

PubMed [citation]
PMID:
20482598

Pathogenic variant burden in the ExAC database: an empirical approach to evaluating population data for clinical variant interpretation.

Kobayashi Y, Yang S, Nykamp K, Garcia J, Lincoln SE, Topper SE.

Genome Med. 2017 Feb 6;9(1):13. doi: 10.1186/s13073-017-0403-7.

PubMed [citation]
PMID:
28166811
PMCID:
PMC5295186
See all PubMed Citations (6)

Details of each submission

From Illumina Clinical Services Laboratory,Illumina, SCV000348007.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

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

From Invitae, SCV000657720.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

This sequence change replaces alanine with threonine at codon 716 of the MFN2 protein (p.Ala716Thr). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs144860227, ExAC 0.04%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported to segregate with dominant intermediate Charcot Marie Tooth disease in a single family (PMID: 20350294) and has been reported in 2 additional individuals affected with Charcot Marie Tooth disease type 2 (PMID: 21508331, 22492563). ClinVar contains an entry for this variant (Variation ID: 214649). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0. The threonine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, this variant has uncertain impact on MFN2 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

Last Updated: Oct 30, 2021

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