NM_004208.4(AIFM1):c.1030C>T (p.Leu344Phe) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Sep 25, 2024
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:: RCV002051816.4

Allele description [Variation Report for NM_004208.4(AIFM1):c.1030C>T (p.Leu344Phe)]

NM_004208.4(AIFM1):c.1030C>T (p.Leu344Phe)

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.1030C>T (p.Leu344Phe)

Other names:

AIFM1, LEU344PHE (rs184474885)

HGVS:

NC_000023.11:g.130137123G>A
NG_013217.1:g.33711C>T
NM_001130846.4:c.13C>T
NM_001130847.4:c.*258C>T
NM_004208.4:c.1030C>TMANE SELECT
NM_145812.3:c.1018C>T
NP_001124318.2:p.Leu5Phe
NP_004199.1:p.Leu344Phe
NP_665811.1:p.Leu340Phe
NC_000023.10:g.129271098G>A
NM_004208.3:c.1030C>T
NR_132647.2:n.1275C>T
O95831:p.Leu344Phe

Protein change:

L340F; LEU344PHE

Links:

UniProtKB: O95831#VAR_076212; OMIM: 300169.0004; dbSNP: rs184474885

NCBI 1000 Genomes Browser:

rs184474885

Molecular consequence:

NM_001130847.4:c.*258C>T - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001130846.4:c.13C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_004208.4:c.1030C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_145812.3:c.1018C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_132647.2:n.1275C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Synonyms:: none provided; RECLASSIFIED - ADRA2C POLYMORPHISM; RECLASSIFIED - ADRB1 POLYMORPHISM
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002319081	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Sep 25, 2024)	germline	clinical testing	Citation Link,
SCV005878152	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Uncertain Significance (Apr 16, 2024)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002319081

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Sep 25, 2024)

germline

clinical testing

Citation Link,

SCV005878152

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process 2024)

Uncertain Significance
(Apr 16, 2024)

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

Details of each submission

From GeneDx, SCV002319081.3

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

Description

Identified as heterozygous in several unrelated Chinese females with bilateral auditory neuropathy in published literature, and in one female with unilateral auditory neuropathy, suggesting possible X-linked dominant inheritance (PMID: 34175691, 32684920); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in 37/14851 (0.2491%) alleles from individuals of East Asian background in large population cohorts (gnomAD); unknown if this represents a pathogenic founder variant or a common benign variant in this population; This variant is associated with the following publications: (PMID: 31832524, Chai_2021_Editorial, 34175691, 32684920, 25986071, 35578252)

#	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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV005878152.1

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

Description

The AIFM1 c.1030C>T; p.Leu344Phe variant (rs184474885, ClinVar Variation ID: 162477) is reported in the literature in individuals affected with auditory neuropathy, including affected heterozygous female patients (Song 2021, Wang 2020, Zong 2015). Additionally, this variant was found in an individual affected with Charcot-Marie-Tooth disease-4 (Chen 2022), and in an infant with focal seizures (Ma 2019). This variant is found in the East Asian population with an allele frequency of 0.25% (37/14,851 alleles, including 20 hemizygotes) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.279). Due to conflicting information, the clinical significance of this variant is uncertain at this time. References: Chen J et al. Genetic origin of patients having spastic paraplegia with or without other neurologic manifestations. BMC Neurol. 2022 May 16;22(1):180. PMID: 35578252. Ma X et al. Genetic diagnosis of neonatal-onset seizures. Genes Dis. 2019 Feb 8;6(4):441-447. PMID: 31832524. Song M et al. Clinical characteristics of patients with unilateral auditory neuropathy. Am J Otolaryngol. 2021 Sep-Oct;42(5):103143. PMID: 34175691. Wang H et al. High Frequency of AIFM1 Variants and Phenotype Progression of Auditory Neuropathy in a Chinese Population. Neural Plast. 2020 Jul 1;2020:5625768. PMID: 32684920. Zong L et al. Mutations in apoptosis-inducing factor cause X-linked recessive auditory neuropathy spectrum disorder. J Med Genet. 2015 Aug;52(8):523-31. PMID: 25986071.

#	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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