NM_014874.4(MFN2):c.227T>C (p.Leu76Pro) AND not provided

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Oct 3, 2022
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:: RCV000200837.18

Allele description [Variation Report for NM_014874.4(MFN2):c.227T>C (p.Leu76Pro)]

NM_014874.4(MFN2):c.227T>C (p.Leu76Pro)

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.227T>C (p.Leu76Pro)

Other names:

p.L76P:CTG>CCG

HGVS:

NC_000001.11:g.11992606T>C
NG_007945.1:g.17426T>C
NM_001127660.2:c.227T>C
NM_014874.4:c.227T>CMANE SELECT
NP_001121132.1:p.Leu76Pro
NP_055689.1:p.Leu76Pro
NP_055689.1:p.Leu76Pro
LRG_255t1:c.227T>C
LRG_255:g.17426T>C
LRG_255p1:p.Leu76Pro
NC_000001.10:g.12052663T>C
NM_014874.3:c.227T>C
O95140:p.Leu76Pro

Protein change:

L76P; LEU76PRO

Links:

UniProtKB: O95140#VAR_018608; OMIM: 608507.0003; dbSNP: rs28940293

NCBI 1000 Genomes Browser:

rs28940293

Molecular consequence:

NM_001127660.2:c.227T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_014874.4:c.227T>C - 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
SCV000251708	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Oct 3, 2022)	germline	clinical testing	Citation Link,
SCV000255678	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Pathogenic (Jul 29, 2022)	unknown	clinical testing	PubMed (13) [See all records that cite these PMIDs] 26968460, 17215403, 20335458, 25614874, 29898954, 10732809, 33415332, 28380071, 15064763, 16714318, 17296794, 31701603, 26467025
SCV000856104	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Pathogenic (Aug 28, 2017)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 10732809, 17215403, 25614874, 15064763, 17296794 Citation Link,
SCV001715251	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 21, 2019)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 15064763, 16714318, 17296794, 26143526, 31127728, 25614874, 10732809, 17215403, 20335458, 25741868

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
not provided	germline	unknown	2	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Zebrafish Tg(hb9:MTS-Kaede): a new in vivo tool for studying the axonal movement of mitochondria.

Bergamin G, Cieri D, Vazza G, Argenton F, Mostacciuolo ML.

Biochim Biophys Acta. 2016 Jun;1860(6):1247-55. doi: 10.1016/j.bbagen.2016.03.007. Epub 2016 Mar 9.

PubMed [citation]

PMID:: 26968460

Mitofusin gain and loss of function drive pathogenesis in Drosophila models of CMT2A neuropathy.

El Fissi N, Rojo M, Aouane A, Karatas E, Poliacikova G, David C, Royet J, Rival T.

EMBO Rep. 2018 Aug;19(8). doi:pii: e45241. 10.15252/embr.201745241. Epub 2018 Jun 13. Erratum in: EMBO Rep. 2020 Jul 3;21(7):e50703. doi: 10.15252/embr.202050703.

PubMed [citation]

PMID:: 29898954
PMCID:: PMC6073211

See all PubMed Citations (16)

Details of each submission

From GeneDx, SCV000251708.15

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

Description

Reported previously as a pathogenic variant in a patient with neuropathy; however, no other clinical information was provided (Lee et al., 2019); Reported as a common pathogenic variant in individuals with Charcot-Marie-Tooth (DiVincenzo et al., 2014); Functional studies suggest the L76P variant results in mitochondrial aggregation and altered mitochondrial mobility and morphology (Baloh et al., 2007; Bergamin et al., 2016; El Fissi et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17296794, 26143526, 10732809, 33049996, 26968460, 20335458, 19584314, 22957060, 25614874, 15064763, 16714318, 29898954, 31127728, 9333264, 28380071, 31096646, Yenkin2022[FunctionalStudy], 31701603, 17215403)

#	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 Athena Diagnostics, SCV000255678.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (13)

Description

The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features of Charcot-Marie-Tooth disease. This variant occurs as the most likely explanation for disease in a significant number of internal cases, suggesting this variant is associated with disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. Studies demonstrate significant changes to mitochondrial function in various model systems (PMID: 20335458, 26968460, 29898954). The variant is located in a region that is considered important for protein function and/or structure.

#	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 Eurofins Ntd Llc (ga), SCV000856104.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (5)

#	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		1	not provided	not provided	not provided

From Mayo Clinic Laboratories, Mayo Clinic, SCV001715251.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (10)

Description

PS3, PS4, PM2, PP1

#	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		1	not provided	not provided	not provided

Last Updated: May 7, 2024

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