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

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000200521	SCV000253930	pathogenic	Charcot-Marie-Tooth disease, type 4A	2019-12-30	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
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 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	RCV001195786	SCV001366206	likely pathogenic	Hypothyroidism; Decreased body weight; Severe intrauterine growth retardation; Severe postnatal growth retardation; Congenital microcephaly	2020-02-03	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP5. This variant was detected in heterozygous state.
Centre for Mendelian Genomics,University Medical Centre Ljubljana	RCV001195881	SCV001366305	likely pathogenic	Hearing impairment; Muscle weakness; Dysphonia; Restrictive deficit on pulmonary function testing; Sensorimotor neuropathy	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP4. This variant was detected in heterozygous state.
Centre for Mendelian Genomics,University Medical Centre Ljubljana	RCV001198738	SCV001369733	pathogenic	Dysphonia; Distal muscle weakness; Progressive inability to walk; Areflexia of lower limbs; Distal sensory impairment of all modalities; Upper limb muscle weakness; Lower limb muscle weakness	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: PS1,PP1,PM2,PP3,PP4. This variant was detected in heterozygous state.
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