Total submissions: 10
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. |
Gene |
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, |
RCV000004418 | SCV000328201 | pathogenic | Charcot-Marie-Tooth disease type 2K | 2016-10-05 | criteria provided, single submitter | clinical testing | |
Ce |
RCV000236074 | SCV001249597 | pathogenic | not provided | 2018-02-01 | criteria provided, single submitter | clinical testing | |
Foundation for Research in Genetics and Endocrinology, |
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, |
RCV000192249 | SCV001336396 | pathogenic | Charcot-Marie-Tooth disease | criteria provided, single submitter | clinical testing | ||
Centre for Mendelian Genomics, |
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. |
OMIM | RCV000004418 | SCV000024591 | pathogenic | Charcot-Marie-Tooth disease type 2K | 2011-08-09 | no assertion criteria provided | literature only | |
Gene |
RCV000004418 | SCV000054654 | pathologic | Charcot-Marie-Tooth disease type 2K | 2012-09-13 | no assertion criteria provided | curation | Converted during submission to Pathogenic. |
Gene |
RCV000192249 | SCV000239897 | pathogenic | Charcot-Marie-Tooth disease | 2015-04-30 | no assertion criteria provided | literature only |