Submissions for variant NM_004208.4(AIFM1):c.1047C>T (p.Ser349=) (rs781350745)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000197100	SCV000251110	benign	not specified	2014-12-29	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Illumina Clinical Services Laboratory,Illumina	RCV000264409	SCV000481726	likely benign	Combined oxidative phosphorylation deficiency 6	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Invitae	RCV000554197	SCV000658925	uncertain significance	Charcot-Marie-Tooth Neuropathy X; Combined oxidative phosphorylation deficiency	2019-09-27	criteria provided, single submitter	clinical testing	This sequence change affects codon 349 of the AIFM1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the AIFM1 protein. This variant is present in population databases (rs781350745, ExAC 0.01%). This variant has not been reported in the literature in individuals with AIFM1-related disease. ClinVar contains an entry for this variant (Variation ID: 214080). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Molecular Genetics Laboratory,London Health Sciences Centre	RCV001173134	SCV001336210	likely benign	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing