ClinVar Miner

Submissions for variant NM_001005360.2(DNM2):c.1384A>G (p.Thr462Ala) (rs201575500)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000489408 SCV000613148 likely benign not specified 2016-06-10 criteria provided, single submitter clinical testing
GeneDx RCV000766564 SCV000577324 uncertain significance not provided 2017-04-04 criteria provided, single submitter clinical testing The T462A variant has been previously reported as a variant of unknown significance in an individual with congenital myopathy who harbored additional variants in other neuromuscular-related genes (Savarese et al., 2014). The T462A variant is observed in 19/66618 (0.03%) alleles from individuals of European background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and missense variant in a nearby residue (R465W) has been reported in the Human Gene Mutation Database in association with centronuclear myopathy (Stenson et al., 2014). In silico analysis predicts this variant is probably damaging to the protein structure/function.
Illumina Clinical Services Laboratory,Illumina RCV000271317 SCV000410365 likely benign Charcot-Marie-Tooth, Intermediate 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000331170 SCV000410366 likely benign Centronuclear Myopathy, Dominant 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000459689 SCV000553368 uncertain significance Charcot-Marie-Tooth disease, dominant intermediate B 2018-10-29 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 462 of the DNM2 protein (p.Thr462Ala). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and alanine. This variant is present in population databases (rs201575500, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in an individual affected with congenital myopathy (PMID: 25214167). ClinVar contains an entry for this variant (Variation ID: 327980). 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: "Tolerated"; 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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