ClinVar Miner

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

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Total submissions: 14
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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 2020-10-08 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 2019-10-30 criteria provided, single submitter clinical testing Published functional analysis showed that R120W impairs mitochondrial function (Zimon et al., 2011; Niemann et al., 2009); Missense variants in nearby residues reported in the Human Gene Mutation Database (Stenson et al., 2014); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 15772096, 22546700, 23628762, 19782751, 26525999, 20301641, 25168384, 21753178, 28379183, 15805163, 14561495, 28673555, 30373780, 31827005, 33136338, 31589614)
Neurology Department,Peking University First Hospital RCV000004418 SCV000328201 pathogenic Charcot-Marie-Tooth disease axonal type 2K 2016-10-05 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000236074 SCV001249597 pathogenic not provided 2018-02-01 criteria provided, single submitter clinical testing
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics RCV001225306 SCV001335304 pathogenic Charcot-Marie-Tooth disease axonal type 2K; Charcot-Marie-Tooth disease, type 4A; Charcot-Marie-Tooth disease, recessive intermediate A 2020-04-20 criteria provided, single submitter clinical testing A heterozygous missense variation in exon 3 of the GDAP1 gene that results in the amino acid substitution of Tryptophan for Arginine at codon 120 was detected. The observed variant c.358C>T(p.Arg120Trp) has previously been reported in heterozygous state in patients affected with Charcot-Marie-Tooth type 4A disease. Experimental studies have shown that this missense change impairs the mitochondrial fusion process and results in dysfunctional mitochondria (Pedrola et al. 2008). The variant has not been reported in the 1000 genomes and ExAC databases. The in silico prediction of the variant are probably damaging by PolyPhen-2 (HumDiv) and damaging by SIFT, LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic.
Molecular Genetics Laboratory,London Health Sciences Centre RCV000192249 SCV001336396 pathogenic Charcot-Marie-Tooth disease criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000200521 SCV001366305 pathogenic Charcot-Marie-Tooth disease, type 4A 2020-03-23 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PS4,PM1,PM2,PP3.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000236074 SCV001762032 pathogenic not provided 2021-06-17 criteria provided, single submitter clinical testing
OMIM RCV000004418 SCV000024591 pathogenic Charcot-Marie-Tooth disease axonal type 2K 2011-08-09 no assertion criteria provided literature only
GeneReviews RCV000004418 SCV000054654 pathologic Charcot-Marie-Tooth disease axonal type 2K 2012-09-13 no assertion criteria provided curation Converted during submission to Pathogenic.
GenomeConnect - Invitae Patient Insights Network RCV001535613 SCV001749634 not provided Charcot-Marie-Tooth disease axonal type 2K; Charcot-Marie-Tooth disease, type 4A; Charcot-Marie-Tooth disease, axonal, with vocal cord paresis, autosomal recessive; Charcot-Marie-Tooth disease, recessive intermediate A no assertion provided phenotyping only Variant interpreted as Pathogenic and reported on 04-05-2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
GeneReviews RCV000192249 SCV001750194 pathogenic Charcot-Marie-Tooth disease 2017-03-30 no assertion criteria provided literature only
Clinical Genetics,Academic Medical Center RCV000236074 SCV001925231 pathogenic not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000236074 SCV001955506 pathogenic not provided no assertion criteria provided clinical testing

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