ClinVar Genomic variation as it relates to human health

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.

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PS4,PM1,PM2,PP3.

The GDAP1 c.358C>T variant is classified as a PATHOGENIC variant (PS3, PS4, PP3) This variant is a single nucleotide change in exon 3/6 of the GDAP1 gene, which is predicted to change the amino acid arginine at position 120 in the protein to tryptophan. The variant has been reported multiple times in individuals with CMT disease and has been observed to segregate with autosomal dominant CMT disease in several families (PMID: 21753178, 15805163, 21199105). The variant is in dbSNP (rs104894078) but is rare in population databases (gnomAD 1/152152, 0 homozygote (PS4). Functional studies have shown that this variant impairs the mitochondrial fusion process and results in dysfunctional mitochondrial (PMID: 21753178, 19782751) (PS3). The variant has been reported in both ClinVar (Variation ID: 4198) and HGMD (Accession: CM032927) as pathogenic. Computational predictions support a deleterious effect on the gene or gene product (PP3).

The GDAP1 c.358C>T; p.Arg120Trp variant (rs104894078), is reported in the literature in multiple individuals affected with Charcot-Marie-Tooth (CMT) disease and has been observed to cosegregate with autosomal dominant disease in several large kindreds (Claramunt 2005, Sivera 2010, Zimon 2011). This variant is found on a single chromosome in the Genome Aggregation Database (1/31398 alleles), indicating it is not a common polymorphism. The arginine at codon 120 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.879). Consistent with these predictions, functional assays demonstrate the variant protein fails to promote mitochondrial fusion like wildtype GDAP1 (Niemann 2009, Zimon 2011). Additionally, another amino acid substitution at the same codon (p.Arg120Gly) has been reported to segregate with autosomal dominant CMT in a large family and is considered disease-causing (Manganelli 2012), suggesting this codon is functionally important. Based on available information, the p.Arg120Trp variant is considered to be pathogenic. References: Claramunt R et al. Genetics of Charcot-Marie-Tooth disease type 4A: mutations, inheritance, phenotypic variability, and founder effect. J Med Genet. 2005 Apr;42(4):358-65. Manganelli F et al. A novel autosomal dominant GDAP1 mutation in an Italian CMT2 family. J Peripher Nerv Syst. 2012 Sep;17(3):351-5. Niemann A et al. GDAP1 mutations differ in their effects on mitochondrial dynamics and apoptosis depending on the mode of inheritance. Neurobiol Dis. 2009 Dec;36(3):509-20. Sivera R et al. Phenotypical features of the p.R120W mutation in the GDAP1 gene causing autosomal dominant Charcot-Marie-Tooth disease. J Peripher Nerv Syst. 2010 Dec;15(4):334-44. Zimon M et al. Dominant GDAP1 mutations cause predominantly mild CMT phenotypes. Neurology. 2011 Aug 9;77(6):540-8.

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 120 of the GDAP1 protein (p.Arg120Trp). This variant is present in population databases (rs104894078, gnomAD 0.007%). This missense change has been observed in individuals with autosomal dominant Charcot-Marie-Tooth disease (PMID: 15805163, 21199105, 21753178). It has also been observed to segregate with disease in related individuals. This variant has been reported in individual(s) with autosomal recessive Charcot-Marie-Tooth disease (PMID: 14561495); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 4198). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects GDAP1 function (PMID: 18021315, 19782751, 21753178, 21890626). For these reasons, this variant has been classified as Pathogenic.

Published functional analysis showed that R120W impairs mitochondrial function (Zimon et al., 2011; Niemann et al., 2009); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 15772096, 22546700, 23628762, 26525999, 20301641, 25168384, 28379183, 14561495, 28673555, 30373780, 33136338, 31589614, 29417091, 35153971, 31655048, 30669311, 35656516, 33187793, 19782751, 31827005, 32153140, 15805163, 21753178, 34323022, 33480199)

Variant summary: GDAP1 c.358C>T (p.Arg120Trp) results in a non-conservative amino acid change in the encoded protein sequence. Three of three in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251462 control chromosomes. c.358C>T has been reported in the literature as segregating with a milder phenotype in multiple individuals affected with features of autosomal dominant Charcot-Marie Disease Type 4A (example, Claramunt_2005, Pezzini_2016). These data indicate that the variant is very likely to be associated with disease. Publications reporting an impact on protein function have been reported (example, Estela_2011). The following publications have been ascertained in the context of this evaluation (PMID: 33136338, 15805163, 21890626, 26525999). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

The p.R120W pathogenic mutation (also known as c.358C>T), located in coding exon 3 of the GDAP1 gene, results from a C to T substitution at nucleotide position 358. The arginine at codon 120 is replaced by tryptophan, an amino acid with dissimilar properties. The p.R120W alteration has been reported to segregate with disease in multiple unrelated families with features of dominantly inherited Charcot-Marie-Tooth disease (CMT; Sivera R et al. J. Peripher. Nerv. Syst., 2010 Dec;15:334-44; Zimo M et al. Neurology, 2011 Aug;77:540-8; Vital A et al. Neuromuscul. Disord., 2012 Aug;22:735-41). Reported patients have a variable phenotype with mild-moderate axonal CMT with typical onset around adolescence, and incomplete penetrance has been reported (Sivera R et al. J. Peripher. Nerv. Syst., 2010 Dec;15:334-44; Vital A et al. Neuromuscul. Disord., 2012 Aug;22:735-41). The mechanism for disease of dominantly inherited forms of GDAP1-related CMT is an interference with mitochondrial fusion, and functional studies showed significant mitochondrial fragmentation and significantly impaired mitochondrial fusion in cells transfected with the p.R120W alteration compared to wildtype (Niemann A et al. Neurobiol. Dis., 2009 Dec;36:509-20; Zimo M et al. Neurology, 2011 Aug;77:540-8). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

GDAP1: PM2, PM5, PS4:Moderate, PP1, PP3, PP4, PS3:Supporting

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.