ClinVar Miner

Submissions for variant NM_014874.4(MFN2):c.1385A>G (p.Tyr462Cys)

dbSNP: rs2100849130
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001974408 SCV002262090 uncertain significance Charcot-Marie-Tooth disease type 2 2024-07-18 criteria provided, single submitter clinical testing This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 462 of the MFN2 protein (p.Tyr462Cys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MFN2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1478913). 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 MFN2 protein function with a positive predictive value of 95%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Baylor Genetics RCV003147723 SCV003834802 uncertain significance Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b; 2022-12-15 criteria provided, single submitter clinical testing
Baylor Genetics RCV003147724 SCV003836013 uncertain significance Neuropathy, hereditary motor and sensory, type 6A 2022-12-15 criteria provided, single submitter clinical testing
Baylor Genetics RCV003147722 SCV003836014 uncertain significance Charcot-Marie-Tooth disease type 2A2 2022-12-15 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003388072 SCV004099570 uncertain significance not specified 2023-09-06 criteria provided, single submitter clinical testing Variant summary: MFN2 c.1385A>G (p.Tyr462Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251496 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1385A>G in individuals affected with MFN2-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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