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

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
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.
CeGaT Praxis fuer Humangenetik Tuebingen	RCV001092877	SCV001249596	pathogenic	not provided	2017-12-01	criteria provided, single submitter	clinical testing
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