VCV000162477.12 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(4)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Uncertain significance(1); Benign(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 162477 Accession: VCV000162477.12

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xq26.1 X: 130137123 (GRCh38) [ NCBI UCSC ] X: 129271098 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jan 18, 2015	Oct 8, 2024	Sep 25, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_004208.4:c.1030C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004199.1:p.Leu344Phe	missense
NM_001130846.4:c.13C>T	NP_001124318.2:p.Leu5Phe	missense
NM_001130847.4:c.*258C>T		3 prime UTR
NM_145812.3:c.1018C>T	NP_665811.1:p.Leu340Phe	missense
NR_132647.2:n.1275C>T		non-coding transcript variant
NC_000023.11:g.130137123G>A
NC_000023.10:g.129271098G>A
NG_013217.1:g.33711C>T
	O95831:p.Leu344Phe

... more HGVS ... less HGVS

Protein change

L344F, L340F, L5F

Other names

AIFM1, LEU344PHE (rs184474885)

Canonical SPDI

NC_000023.11:130137122:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00053 (A)

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00004

The Genome Aggregation Database (gnomAD), exomes 0.00019

Trans-Omics for Precision Medicine (TOPMed) 0.00019

Exome Aggregation Consortium (ExAC) 0.00021

1000 Genomes Project 0.00053

1000 Genomes Project 30x 0.00062

Links

ClinGen: CA175062 UniProtKB: O95831#VAR_076212 OMIM: 300169.0004 dbSNP: rs184474885 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
AIFM1		-	-	GRCh38 GRCh37	7	667
RAB33A		-	-	GRCh38 GRCh37	9	668

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Deafness, X-linked 5	Pathogenic/Likely pathogenic (2)	no assertion criteria provided	Aug 1, 2015	RCV000149862.3
Charcot-Marie-Tooth Neuropathy X Combined oxidative phosphorylation deficiency	Benign (1)	criteria provided, single submitter	Dec 17, 2023	RCV000868580.9
not provided	Uncertain significance (1)	criteria provided, single submitter	Sep 25, 2024	RCV002051816.3

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Benign (Dec 17, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Charcot-Marie-Tooth Neuropathy X Combined oxidative phosphorylation deficiency Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001009925.6 First in ClinVar: Dec 17, 2019 Last updated: Feb 28, 2024
Uncertain significance (Sep 25, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002319081.3 First in ClinVar: Apr 02, 2022 Last updated: Oct 08, 2024	Comment: 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 … (more) 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) (less)
Likely pathogenic (-)	no assertion criteria provided Method: clinical testing	Deafness, X-linked 5 (Sporadic) Affected status: yes Allele origin: unknown	Deafness Gene Diagnosis, Xijing Hospital Accession: SCV000196716.1 First in ClinVar: Jan 18, 2015 Last updated: Jan 18, 2015 Comment: missense mutation in conserved position, not detected in normal control (118 people), and Mutationtaster predicted as Disease Causing	Number of individuals with the variant: 1 Clinical Features: auditory neuropathy (present) Family history: no Age: 20-29 years Sex: male Geographic origin: China Tissue: blood
Pathogenic (Aug 01, 2015)	no assertion criteria provided Method: literature only	DEAFNESS, X-LINKED 5 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000257353.2 First in ClinVar: Jan 18, 2015 Last updated: Sep 21, 2016	Publications: PubMed (1) PubMed: 25986071 Comment on evidence: In 2 Chinese brothers (family 0223) with X-linked deafness-5 (DFNX5; 300614), Zong et al. (2015) identified a hemizygous c.1030C-T transition (rs184474885) in exon 10 of … (more) In 2 Chinese brothers (family 0223) with X-linked deafness-5 (DFNX5; 300614), Zong et al. (2015) identified a hemizygous c.1030C-T transition (rs184474885) in exon 10 of the AIFM1 gene, resulting in a leu344-to-phe (L344F) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was annotated in the dbSNP (build 141) database at a very low frequency (0.0005), but was not found in 500 Chinese controls. Screening for AIFM1 mutations in 93 unrelated patients with sporadic auditory neuropathy revealed that 3 additional unrelated patients carried the L344F mutation. Functional studies of the variant were not performed. (less)

Comment:

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)

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Mutations in apoptosis-inducing factor cause X-linked recessive auditory neuropathy spectrum disorder.	Zong L	Journal of medical genetics	2015	PMID: 25986071

Text-mined citations for rs184474885 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 08, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs184474885 ...