ClinVar Miner

Submissions for variant NM_014874.3(MFN2):c.179C>T (p.Thr60Met) (rs138345244)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236416 SCV000294093 uncertain significance not provided 2016-03-28 criteria provided, single submitter clinical testing The T60M variant has notbeen published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge.The T60M variant was not observed with any significant frequency in approximately 6,500individuals of European and African American ancestry in the NHLBI Exome Sequencing Project butthe 1000 Genomes Project reports T60M was observed in 2/1008 (0.02%) alleles from individuals ofEast Asian background. This substitution occurs at a position that is conserved across species. TheT60M variant is a non-conservative amino acid substitution, which is likely to impact secondaryprotein structure as these residues differ in polarity, charge, size and/or other properties. However, insilico analysis is inconsistent in its predictions as to whether or not the variant is damaging to theprotein structure/function. Therefore, based on the currently available information, it is unclearwhether this variant is a pathogenic variant or a rare benign variant.
Illumina Clinical Services Laboratory,Illumina RCV000653930 SCV000347972 likely benign Charcot-Marie-Tooth disease, type 2 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.
Illumina Clinical Services Laboratory,Illumina RCV000275642 SCV000347973 benign Hereditary motor and sensory neuropathy with optic atrophy 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Invitae RCV000653930 SCV000775820 uncertain significance Charcot-Marie-Tooth disease, type 2 2019-09-19 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 60 of the MFN2 protein (p.Thr60Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs138345244, ExAC 0.02%). This variant has not been reported in the literature in individuals with MFN2-related disease. ClinVar contains an entry for this variant (Variation ID: 246508). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.

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