Submissions for variant NM_004208.4(AIFM1):c.1120G>A (p.Val374Ile)

dbSNP: rs1057521792

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000440195	SCV000524563	uncertain significance	not provided	2016-02-22	criteria provided, single submitter	clinical testing	The V374I variant in the AIFM1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The V374I variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The V374I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret V374I as a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001861539	SCV002190874	uncertain significance	Charcot-Marie-Tooth Neuropathy X; Combined oxidative phosphorylation deficiency	2021-11-28	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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 not expected to disrupt AIFM1 protein function. ClinVar contains an entry for this variant (Variation ID: 383941). This variant has not been reported in the literature in individuals affected with AIFM1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 374 of the AIFM1 protein (p.Val374Ile).
PreventionGenetics, part of Exact Sciences	RCV004748757	SCV005364533	uncertain significance	AIFM1-related disorder	2024-08-29	no assertion criteria provided	clinical testing	The AIFM1 c.1120G>A variant is predicted to result in the amino acid substitution p.Val374Ile. To our knowledge, this variant has not been reported in the literature or in a large population database (gnomAD v2.1.1), indicating this variant is rare. However, this variant has been reported in the larger gnomAD v.4.1.0 database in three alleles including one hemizygote (https://gnomad.broadinstitute.org/variant/X-130136687-C-T?dataset=gnomad_r4). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.