ClinVar Miner

Submissions for variant NM_018972.4(GDAP1):c.347T>G (p.Met116Arg) (rs281865060)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneReviews RCV000031962 SCV000054653 pathologic Charcot-Marie-Tooth disease, type 4A 2012-09-13 no assertion criteria provided curation Converted during submission to Pathogenic.
Inherited Neuropathy Consortium RCV000789791 SCV000929175 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only
Invitae RCV000031962 SCV000644067 pathogenic Charcot-Marie-Tooth disease, type 4A 2018-07-09 criteria provided, single submitter clinical testing This sequence change replaces methionine with arginine at codon 116 of the GDAP1 protein (p.Met116Arg). The methionine residue is moderately conserved and there is a moderate physicochemical difference between methionine and arginine. This variant is present in population databases (rs281865060, ExAC 0.006%). This variant has been reported as homozygous or in combination with another GDAP1 variant in several individuals affected with autosomal recessive Charcot-Marie-Tooth disease (PMID: 15377708, 25429913). This variant has been reported to segregate with Charcot-Marie-Tooth disease in a single family (PMID: 15377708). ClinVar contains an entry for this variant (Variation ID: 38411). Experimental studies have shown that this missense change is able to protect against oxidative glutamate toxicity to a lesser degree compared to wild-type (PMID: 21965300). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.

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