ClinVar Miner

Submissions for variant NM_018972.4(GDAP1):c.556A>G (p.Ile186Val) (rs148508128)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Praxis fuer Humangenetik Tuebingen RCV000416100 SCV000493443 uncertain significance not provided 2016-07-31 criteria provided, single submitter clinical testing
GeneDx RCV000416100 SCV000279436 uncertain significance not provided 2016-03-22 criteria provided, single submitter clinical testing The I186V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The I186V variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project or in the 1000 Genomes Project. The I186V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Isoleucine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000200426 SCV000255035 uncertain significance Charcot-Marie-Tooth disease, type 4A 2018-12-14 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 186 of the GDAP1 protein (p.Ile186Val). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs148508128, ExAC 0.05%). This variant has not been reported in the literature in individuals with GDAP1-related disease. ClinVar contains an entry for this variant (Variation ID: 216707). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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