NM_014874.4(MFN2):c.281G>A (p.Arg94Gln) AND not provided

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jan 1, 2023
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:: RCV000286431.20

Allele description

NM_014874.4(MFN2):c.281G>A (p.Arg94Gln)

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.281G>A (p.Arg94Gln)

Other names:

chr1-11992660-G-A

HGVS:

NC_000001.11:g.11992660G>A
NG_007945.1:g.17480G>A
NM_001127660.2:c.281G>A
NM_014874.4:c.281G>AMANE SELECT
NP_001121132.1:p.Arg94Gln
NP_001121132.1:p.Arg94Gln
NP_055689.1:p.Arg94Gln
NP_055689.1:p.Arg94Gln
LRG_255t1:c.281G>A
LRG_255:g.17480G>A
LRG_255p1:p.Arg94Gln
NC_000001.10:g.12052717G>A
NM_001127660.1:c.281G>A
NM_014874.3:c.281G>A
O95140:p.Arg94Gln

Protein change:

R94Q; ARG94GLN

Links:

UniProtKB: O95140#VAR_018609; OMIM: 608507.0001; dbSNP: rs28940291

NCBI 1000 Genomes Browser:

rs28940291

Molecular consequence:

NM_001127660.2:c.281G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_014874.4:c.281G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000255680	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Pathogenic (Oct 6, 2021)	unknown	clinical testing	PubMed (18) [See all records that cite these PMIDs] 17437620, 20335458, 26230519, 17296794, 30882371, 29898954, 17215403, 16714318, 15549395, 19812251, 20350294, 22492563, 15064763, 18996695, 19889647, 20418531, 21285398, 26467025
SCV000329569	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Mar 24, 2022)	germline	clinical testing	Citation Link,
SCV003916053	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Jan 1, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000255680

Athena Diagnostics

criteria provided, single submitter

(Athena Diagnostics Criteria)

Pathogenic
(Oct 6, 2021)

unknown

clinical testing

PubMed (18)
[See all records that cite these PMIDs]

SCV000329569

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Mar 24, 2022)

germline

clinical testing

Citation Link,

SCV003916053

CeGaT Center for Human Genetics Tuebingen

criteria provided, single submitter

(CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)

Pathogenic
(Jan 1, 2023)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mitofusin 2 gene mutation (R94Q) causing severe early-onset axonal polyneuropathy (CMT2A).

Neusch C, Senderek J, Eggermann T, Elolff E, Bähr M, Schneider-Gold C.

Eur J Neurol. 2007 May;14(5):575-7.

PubMed [citation]

PMID:: 17437620

Mitofusin 2 is necessary for transport of axonal mitochondria and interacts with the Miro/Milton complex.

Misko A, Jiang S, Wegorzewska I, Milbrandt J, Baloh RH.

J Neurosci. 2010 Mar 24;30(12):4232-40. doi: 10.1523/JNEUROSCI.6248-09.2010.

PubMed [citation]

PMID:: 20335458
PMCID:: PMC2852190

See all PubMed Citations (18)

Details of each submission

From Athena Diagnostics, SCV000255680.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (18)

Description

The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been confirmed to occur de novo in multiple individuals with clinical features associated with this gene (PMID: 20350294, 17437620). At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. Mouse models expressing this variant induced a CMT2A phenotype and impaired ATP synthesis (PMID 21285398). Based on internal data, this variant occurs with an alternate explanation for disease significantly less often than expected, suggesting this variant may be associated with disease.

#	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, SCV000329569.8

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

Description

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate that this variant induces a drastic decrease in ATP synthesis, suppresses mitochondrial fusion and transport, and results in axonal degeneration (Guillet et al., 2011; Misko et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20418531, 30340945, 18996695, 17437620, 31211173, 24957169, 25025039, 21285398, 22442078, 24604904, 15064763, 29266326, 31640251, 30882369, 30882371, 34103343, 24863639, 20350294, 19889647, 19812251, 17296794, 16714318, 15549395, 29898954, 31832804, 22492563, 21508331, 17215403, 34698563, 32147437, 34128983)

#	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

From CeGaT Center for Human Genetics Tuebingen, SCV003916053.10

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

#	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		1	not provided	not provided	not provided

Last Updated: Jul 15, 2024

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