NM_004208.4(AIFM1):c.1006G>A (p.Glu336Lys) AND multiple conditions

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Nov 2, 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:: RCV000795040.8

Allele description [Variation Report for NM_004208.4(AIFM1):c.1006G>A (p.Glu336Lys)]

NM_004208.4(AIFM1):c.1006G>A (p.Glu336Lys)

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.1006G>A (p.Glu336Lys)

HGVS:

NC_000023.11:g.130137147C>T
NG_013217.1:g.33687G>A
NM_001130846.4:c.-12G>A
NM_001130847.4:c.*234G>A
NM_004208.4:c.1006G>AMANE SELECT
NM_145812.3:c.994G>A
NP_004199.1:p.Glu336Lys
NP_665811.1:p.Glu332Lys
NC_000023.10:g.129271122C>T
NM_004208.3:c.1006G>A
NR_132647.2:n.1251G>A

Protein change:

E332K

Links:

dbSNP: rs1603223158

NCBI 1000 Genomes Browser:

rs1603223158

Molecular consequence:

NM_001130847.4:c.*234G>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001130846.4:c.-12G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_004208.4:c.1006G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_145812.3:c.994G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_132647.2:n.1251G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Functional consequence:

unknown functional consequence

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
SCV000934480	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Nov 2, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000934480

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Nov 2, 2023)

germline

clinical testing

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

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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000934480.6

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

Description

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 336 of the AIFM1 protein (p.Glu336Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of AIFM1-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 641733). 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 with a positive predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

#	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: Sep 29, 2024

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