ClinVar Miner

Submissions for variant NM_018972.4(GDAP1):c.109T>A (p.Ser37Thr) (rs756121249)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000489068 SCV000577469 likely pathogenic not provided 2017-03-28 criteria provided, single submitter clinical testing A variant that is likely pathogenic has been identified in the GDAP1 gene. The S37T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The S37T variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a conserved position predicted to be within the GST N-terminal domain. Missense variants at other residues in the GST domain have been reported in Human Gene Mutation Database in association with GDAP1-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. However, the S37T variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Ambry Genetics RCV000624091 SCV000742917 uncertain significance Inborn genetic diseases 2017-10-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: UNCERTAIN: Alteration(s) of Uncertain Clinical Significance Detected
Invitae RCV000643969 SCV000765656 uncertain significance Charcot-Marie-Tooth disease, type 4A 2017-11-27 criteria provided, single submitter clinical testing This sequence change replaces serine with threonine at codon 37 of the GDAP1 protein (p.Ser37Thr). The serine residue is moderately conserved and there is a small physicochemical difference between serine and threonine. This variant is present in population databases (rs756121249, ExAC 0.001%). This variant has not been reported in the literature in individuals with GDAP1-related disease. ClinVar contains an entry for this variant (Variation ID: 426898). 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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