NM_004208.4(AIFM1):c.1019T>C (p.Met340Thr) AND Charcot-Marie-Tooth disease X-linked recessive 4

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Dec 10, 2019
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

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:: RCV000789722.6

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 disease X-linked recessive 4 (CMTX4)
Synonyms:: Cowchock syndrome; CMTX 4; Neuropathy, axonal motor-sensory with deafness and mental retardation; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0010689; MedGen: C0795910; Orphanet: 101078; OMIM: 310490

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000929099	Inherited Neuropathy Consortium	no assertion criteria provided	Uncertain significance	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV001052585	OMIM	no assertion criteria provided	Pathogenic (Dec 10, 2019)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 28967629, 31523922

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000929099

Inherited Neuropathy Consortium

no assertion criteria provided

Uncertain significance

germline

literature only

PubMed (1)
[See all records that cite this PMID]

SCV001052585

OMIM

no assertion criteria provided

Pathogenic
(Dec 10, 2019)

germline

literature only

PubMed (2)
[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	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	literature only

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

Mutations in AIFM1 cause an X-linked childhood cerebellar ataxia partially responsive to riboflavin.

Heimer G, Eyal E, Zhu X, Ruzzo EK, Marek-Yagel D, Sagiv D, Anikster Y, Reznik-Wolf H, Pras E, Oz Levi D, Lancet D, Ben-Zeev B, Nissenkorn A.

Eur J Paediatr Neurol. 2018 Jan;22(1):93-101. doi: 10.1016/j.ejpn.2017.09.004. Epub 2017 Sep 15.

PubMed [citation]

PMID:: 28967629

See all PubMed Citations (3)

Details of each submission

From Inherited Neuropathy Consortium, SCV000929099.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

#	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 OMIM, SCV001052585.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

In a 17-year-old boy (patient 1) with X-linked recessive Charcot-Marie-Tooth disease-4 with cerebellar ataxia (CMTX4; 310490), Heimer et al. (2018) identified a c.1019T-C transition in the AIFM1 gene, resulting in a met340-to-thr (M340T) substitution at a highly conserved residue close to the NAD binding site. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was inherited from the unaffected mother. It was filtered against the dbSNP (build 138), 1000 Genomes Project, Exome Sequencing Project, and ExAC databases, as well as in-house controls. Functional studies of the variant and studies of patient cells were not performed.

In 7 affected males from a multigenerational Irish family with CMTX4 with cerebellar ataxia, Bogdanova-Mihaylova et al. (2019) identified a hemizygous M340T mutation. The mutation, which was found by whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed.

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

Last Updated: Apr 15, 2024

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