NM_004208.4(AIFM1):c.1265G>A (p.Arg422Gln) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jul 28, 2023
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:: RCV003764900.3

Allele description [Variation Report for NM_004208.4(AIFM1):c.1265G>A (p.Arg422Gln)]

NM_004208.4(AIFM1):c.1265G>A (p.Arg422Gln)

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.1265G>A (p.Arg422Gln)

HGVS:

NC_000023.11:g.130136085C>T
NG_013217.1:g.34749G>A
NM_001130846.4:c.248G>A
NM_001130847.4:c.*493G>A
NM_004208.4:c.1265G>AMANE SELECT
NM_145812.3:c.1253G>A
NP_001124318.2:p.Arg83Gln
NP_004199.1:p.Arg422Gln
NP_665811.1:p.Arg418Gln
NC_000023.10:g.129270060C>T
NM_004208.3:c.1265G>A
NR_132647.2:n.1510G>A
O95831:p.Arg422Gln

Protein change:

R418Q; ARG422GLN

Links:

UniProtKB: O95831#VAR_076214; OMIM: 300169.0007; dbSNP: rs724160021

NCBI 1000 Genomes Browser:

rs724160021

Molecular consequence:

NM_001130847.4:c.*493G>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001130846.4:c.248G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_004208.4:c.1265G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_145812.3:c.1253G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_132647.2:n.1510G>A - 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
SCV004571544	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 28, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 31850270, 25986071, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004571544

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jul 28, 2023)

germline

clinical testing

PubMed (3)
[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

Brief Report of Variants Detected in Hereditary Hearing Loss Cases in Iran over a 3-Year Period.

Bazazzadegan N, Vazehan R, Fadaee M, Fattahi Z, Abolhassani A, Parsimehr E, Kalhor Z, Faraji Zonooz M, Ahangari F, Dehdahsi S, Samiee F, Jamali P, Habibi H, Nourizadeh Y, Mahdavi S, Beheshtian M, Kariminejad A, Smith RJ, Najmabadi H.

Iran J Public Health. 2019 Oct;48(10):1910-1915.

PubMed [citation]

PMID:: 31850270
PMCID:: PMC6908923

Mutations in apoptosis-inducing factor cause X-linked recessive auditory neuropathy spectrum disorder.

Zong L, Guan J, Ealy M, Zhang Q, Wang D, Wang H, Zhao Y, Shen Z, Campbell CA, Wang F, Yang J, Sun W, Lan L, Ding D, Xie L, Qi Y, Lou X, Huang X, Shi Q, Chang S, Xiong W, Yin Z, et al.

J Med Genet. 2015 Aug;52(8):523-31. doi: 10.1136/jmedgenet-2014-102961. Epub 2015 May 18.

PubMed [citation]

PMID:: 25986071
PMCID:: PMC4518735

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004571544.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg422 amino acid residue in AIFM1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25986071, 31850270). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. ClinVar contains an entry for this variant (Variation ID: 162480). This missense change has been observed in individual(s) with clinical features of AIFM1-related conditions (PMID: 25986071). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 422 of the AIFM1 protein (p.Arg422Gln).

#	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: May 16, 2025

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