ClinVar Miner

Submissions for variant NM_018972.4(GDAP1):c.248G>C (p.Gly83Ala) (rs371138642)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000143823 SCV000293007 uncertain significance not provided 2015-07-30 criteria provided, single submitter clinical testing The G83A variant has not been published as pathogenic, nor has it been reported as a benign polymorphism to our knowledge. It was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. This substitution occurs at a position that is conserved in mammals. However, the G83A 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, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000643967 SCV000765654 uncertain significance Charcot-Marie-Tooth disease, type 4A 2018-09-19 criteria provided, single submitter clinical testing This sequence change replaces glycine with alanine at codon 83 of the GDAP1 protein (p.Gly83Ala). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and alanine. This variant is present in population databases (rs371138642, ExAC 0.009%). This variant has not been reported in the literature in individuals with GDAP1-related disease. ClinVar contains an entry for this variant (Variation ID: 155752). Experimental studies have shown that the overexpression of this missense change demonstrated similar mitochondrial morphology and mitochondrial fragmentation to wild type protein (PMID: 18021315). 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.
Northcott Neuroscience Laboratory, ANZAC Research Institute RCV000143823 SCV000188717 non-pathogenic not provided no assertion criteria provided not provided Converted during submission to Benign.

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