NM_004208.4(AIFM1):c.1019T>C (p.Met340Thr) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jun 2, 2021
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:: RCV001385157.9

Allele description [Variation Report for NM_004208.4(AIFM1):c.1019T>C (p.Met340Thr)]

NM_004208.4(AIFM1):c.1019T>C (p.Met340Thr)

Genes:

RAB33A:RAB33A, member RAS oncogene family [Gene - OMIM - HGNC]
AIFM1:apoptosis inducing factor mitochondria associated 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xq26.1

Genomic location:

Preferred name:

NM_004208.4(AIFM1):c.1019T>C (p.Met340Thr)

HGVS:

NC_000023.11:g.130137134A>G
NG_013217.1:g.33700T>C
NM_001130846.4:c.2T>C
NM_001130847.4:c.*247T>C
NM_004208.4:c.1019T>CMANE SELECT
NM_145812.3:c.1007T>C
NP_001124318.2:p.Met1Thr
NP_004199.1:p.Met340Thr
NP_665811.1:p.Met336Thr
NC_000023.10:g.129271109A>G
NM_004208.3:c.1019T>C
NR_132647.2:n.1264T>C

Protein change:

M1T; MET340THR

Links:

OMIM: 300169.0015; dbSNP: rs1057518895

NCBI 1000 Genomes Browser:

rs1057518895

Molecular consequence:

NM_001130847.4:c.*247T>C - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001130846.4:c.2T>C - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_001130846.4:c.2T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_004208.4:c.1019T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_145812.3:c.1007T>C - missense variant - [Sequence Ontology: SO:0001583]
NR_132647.2:n.1264T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Charcot-Marie-Tooth Neuropathy X
Identifiers:: MedGen: CN118851

Name:: Combined oxidative phosphorylation deficiency
Identifiers:: MONDO: MONDO:0000732; MedGen: C4540031; OMIM: PS609060

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001584918	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 2, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 25590979, 31523922, 28967629, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001584918

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jun 2, 2021)

germline

clinical testing

PubMed (4)
[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

Whole-exome sequencing in undiagnosed genetic diseases: interpreting 119 trios.

Zhu X, Petrovski S, Xie P, Ruzzo EK, Lu YF, McSweeney KM, Ben-Zeev B, Nissenkorn A, Anikster Y, Oz-Levi D, Dhindsa RS, Hitomi Y, Schoch K, Spillmann RC, Heimer G, Marek-Yagel D, Tzadok M, Han Y, Worley G, Goldstein J, Jiang YH, Lancet D, et al.

Genet Med. 2015 Oct;17(10):774-81. doi: 10.1038/gim.2014.191. Epub 2015 Jan 15.

PubMed [citation]

PMID:: 25590979
PMCID:: PMC4791490

Clinical spectrum of AIFM1-associated disease in an Irish family, from mild neuropathy to severe cerebellar ataxia with colour blindness.

Bogdanova-Mihaylova P, Alexander MD, Murphy RP, Chen H, Healy DG, Walsh RA, Murphy SM.

J Peripher Nerv Syst. 2019 Dec;24(4):348-353. doi: 10.1111/jns.12348. Epub 2019 Oct 10.

PubMed [citation]

PMID:: 31523922

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001584918.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

For these reasons, this variant has been classified as Pathogenic. 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) performed at Invitae indicates that this missense variant is expected to disrupt AIFM1 protein function. This variant has been observed in individual(s) with clinical features of Charcot-Marie-Tooth disease (PMID: 25590979, 31523922, 28967629). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 374094). This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with threonine at codon 340 of the AIFM1 protein (p.Met340Thr). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and threonine.

#	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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