Submissions for variant NM_018972.4(GDAP1):c.358C>T (p.Arg120Trp) (rs104894078)

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000236074	SCV000292558	pathogenic	not provided	2017-04-13	criteria provided, single submitter	clinical testing	The R120W missense variant in the GDAP1 gene has been reported previously in a patient with Charcot-Marie-Tooth neuropathy; however it was unclear if the variant was acting in a dominant or recessive manner (Ammar et al., 2003). The R120W variant has also been reported to be associated with autosomal dominant CMT2 in multiple unrelated families, and functional analysis showed that R120W impairs mitochondrial function (Claramunt et al., 2005; Niemann et al., 2009; Zimon et al., 2011). Additionally, other amino acid substitutions at this position (R120G/Q) have been published in association with GDAP1-related neuropathy (Stenson et al., 2014). R120W is a non-conservative amino acid substitution that alters a highly conserved position in the GDAP1 protein. Therefore, R120W is interpreted to be a pathogenic variant and its presence may be consistent with the diagnosis in this individual.
GeneReviews	RCV000004418	SCV000054654	pathologic	Charcot-Marie-Tooth disease type 2K	2012-09-13	no assertion criteria provided	curation	Converted during submission to Pathogenic.
GeneReviews	RCV000192249	SCV000239897	pathogenic	Charcot-Marie-Tooth disease	2015-04-30	no assertion criteria provided	literature only
Invitae	RCV000200521	SCV000253930	pathogenic	Charcot-Marie-Tooth disease, type 4A	2018-12-04	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with tryptophan at codon 120 of the GDAP1 protein (p.Arg120Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with autosomal dominant Charcot-Marie-Tooth in multiple families (PMID: 21199105, 15805163, 21753178). In one individual with early onset disease, it was observed in trans with a second pathogenic GDAP1 missense (p.Gly271Arg) variant (PMID: 14561495). ClinVar contains an entry for this variant (Variation ID: 4198). Experimental studies have shown that this missense change impairs the mitochondrial fusion process and results in dysfunctional mitochondria (PMID: 19782751, 21753178, 21890626, 18021315) This variant disrupts the p.Arg120 amino acid residue in GDAP1. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 22971097, 12601710), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Neurology Department,Peking University First Hospital	RCV000004418	SCV000328201	pathogenic	Charcot-Marie-Tooth disease type 2K	2016-10-05	criteria provided, single submitter	clinical testing
OMIM	RCV000004418	SCV000024591	pathogenic	Charcot-Marie-Tooth disease type 2K	2011-08-09	no assertion criteria provided	literature only