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

Total submissions: 14

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