ClinVar Miner

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

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
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.
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
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

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