ClinVar Miner

Submissions for variant NM_001005360.2(DNM2):c.1609G>A (p.Gly537Ser) (rs121909093)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235229 SCV000293785 likely pathogenic not provided 2018-02-28 criteria provided, single submitter clinical testing A variant that is likely pathogenic has been identified in the DNM2 gene. The G537S variant has notbeen published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge.The G537S variant is not observed in large population cohorts (Lek et al., 2016; 1000 GenomesConsortium et al., 2015; Exome Variant Server). The G537S variant is a non-conservative amino acidsubstitution, 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 acrossspecies. In silico analysis predicts this variant is probably damaging to the protein structure/function.Additionally, a different amino acid substitution at the same position (G573C) and another missensevariant in a nearby residue have been reported in the Human Gene Mutation Database in associationwith DNM2-related disorders (Stenson et al., 2014), supporting the functional importance of thisregion of the protein. Therefore, this variant is likely pathogenic; however, the possibility that it isbenign cannot be excluded.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000415354 SCV000492700 likely pathogenic Sensorimotor neuropathy 2015-08-05 criteria provided, single submitter clinical testing
Invitae RCV000641104 SCV000762726 likely pathogenic Charcot-Marie-Tooth disease, dominant intermediate B 2017-11-14 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 537 of the DNM2 protein (p.Gly537Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to be de novo in an individual affected with Charcot-Marie-Tooth disease type 2 (CMT2) (Invitae). ClinVar contains an entry for this variant (Variation ID: 246295). 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: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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