NM_014874.4(MFN2):c.1126A>G (p.Met376Val) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Feb 5, 2021
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001552650.12

Allele description [Variation Report for NM_014874.4(MFN2):c.1126A>G (p.Met376Val)]

NM_014874.4(MFN2):c.1126A>G (p.Met376Val)

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.1126A>G (p.Met376Val)

HGVS:

NC_000001.11:g.12002069A>G
NG_007945.1:g.26889A>G
NM_001127660.2:c.1126A>G
NM_014874.4:c.1126A>GMANE SELECT
NP_001121132.1:p.Met376Val
NP_055689.1:p.Met376Val
NP_055689.1:p.Met376Val
LRG_255t1:c.1126A>G
LRG_255:g.26889A>G
LRG_255p1:p.Met376Val
NC_000001.10:g.12062126A>G
NM_014874.3:c.1126A>G

Protein change:

M376V

Links:

dbSNP: rs863224967

NCBI 1000 Genomes Browser:

rs863224967

Molecular consequence:

NM_001127660.2:c.1126A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_014874.4:c.1126A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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GSM2579093[Accession] (3)
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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000255675	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics criteria)	Pathogenic (Feb 5, 2021)	unknown	clinical testing	PubMed (11) [See all records that cite these PMIDs] 28251916, 26801520, 24473995, 22851605, 30649465, 31664033, 22926664, 22492563, 29674596, 19889647, 26467025
SCV001773375	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Dec 16, 2019)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000255675

Athena Diagnostics

criteria provided, single submitter

(Athena Diagnostics criteria)

Pathogenic
(Feb 5, 2021)

unknown

clinical testing

PubMed (11)
[See all records that cite these PMIDs]

SCV001773375

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely pathogenic
(Dec 16, 2019)

germline

clinical testing

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Genetic heterogeneity of motor neuropathies.

Bansagi B, Griffin H, Whittaker RG, Antoniadi T, Evangelista T, Miller J, Greenslade M, Forester N, Duff J, Bradshaw A, Kleinle S, Boczonadi V, Steele H, Ramesh V, Franko E, Pyle A, Lochmüller H, Chinnery PF, Horvath R.

Neurology. 2017 Mar 28;88(13):1226-1234. doi: 10.1212/WNL.0000000000003772. Epub 2017 Mar 1.

PubMed [citation]

PMID:: 28251916
PMCID:: PMC5373778

Xie Y, Li X, Liu L, Hu Z, Huang S, Zhan Y, Zi X, Xia K, Tang B, Zhang R.

J Peripher Nerv Syst. 2016 Mar;21(1):38-44. doi: 10.1111/jns.12159.

PubMed [citation]

PMID:: 26801520

See all PubMed Citations (11)

Details of each submission

From Athena Diagnostics, SCV000255675.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

This variant was not reported in large, multi-ethnic, general populations (http://gnomad.broadinstitute.org). This variant appears to occur de novo in multiple individuals with clinical features associated with this gene. Assessment of experimental evidence regarding the effect of this variant on protein function is inconclusive. Although there were changes to ER-mitochondrial connectivity and mitochondria-associated ER membranes (MAM) function, this study used patient-derived cells and results could be influenced by factors other than this variant (PMID: 30649465).

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

From GeneDx, SCV001773375.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Not observed in large population cohorts (Lek et al., 2016); Reported as pathogenic in ClinVar but additional evidence is not available (ClinVar SCV# SCV000932432.1; Landrum et al., 2016); Different missense changes at this residue (M376T/R/I) have been reported in association with CMT2 (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30649465, 28251916, 26094742, 19889647, 24473995, 26801520, 23381770, 22492563, 22926664)

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

Last Updated: Jul 15, 2024

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