Submissions for variant NM_018972.4(GDAP1):c.769C>T (p.Arg257Ter)

gnomAD frequency: 0.00001  dbSNP: rs770501034

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000235362	SCV000292560	likely pathogenic	not provided	2024-09-18	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation, as the last 102 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 21322820, 31589614, 31069529, 29858556)
CeGaT Center for Human Genetics Tuebingen	RCV000235362	SCV001249599	pathogenic	not provided	2017-08-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001206561	SCV001377874	pathogenic	Charcot-Marie-Tooth disease type 4A	2024-04-09	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg257*) in the GDAP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 102 amino acid(s) of the GDAP1 protein. This variant is present in population databases (rs770501034, gnomAD 0.007%). This premature translational stop signal has been observed in individuals with clinical features of autosomal recessive GDAP1-related conditions (PMID: 21322820). ClinVar contains an entry for this variant (Variation ID: 245608). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the GDAP1 protein in which other variant(s) (p.Phe263Leufs*22, p.Arg341Glnfs*12) have been determined to be pathogenic (PMID: 12499475, 25614874; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV000664207	SCV002072943	pathogenic	Charcot-Marie-Tooth disease recessive intermediate A		criteria provided, single submitter	clinical testing	The stop gained p.R257* in GDAP1 (NM_018972.4) has been reported previously in affected individuals (DiVincenzo C et al). The variant has been submitted to ClinVar as Pathogenic. The p.R257* variant is observed in 3 individuals in gnomAD Exomes (0.001%) and is novel (not in any individuals) in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001206561	SCV004037648	pathogenic	Charcot-Marie-Tooth disease type 4A	2023-08-28	criteria provided, single submitter	clinical testing	Variant summary: GDAP1 c.769C>T (p.Arg257X) results in a premature termination codon, predicted to cause a truncation of the encoded protein, a commonly known mechanism for disease. Variants downstream of this position have been classified as pathogenic in ClinVar. The variant allele was found at a frequency of 1.2e-05 in 251470 control chromosomes (gnomAD). c.769C>T has been reported in the literature as a biallelic genotype in individuals affected with Charcot-Marie Disease Type 4A (e.g. Karakaya_2018, Ganapathy_2019). These data indicate that the variant is likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31069529, 29858556). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Human Genetics, Cologne University	RCV000664207	SCV000787765	pathogenic	Charcot-Marie-Tooth disease recessive intermediate A	2018-04-25	no assertion criteria provided	clinical testing
Inherited Neuropathy Consortium	RCV000789164	SCV000928516	uncertain significance	Charcot-Marie-Tooth disease		no assertion criteria provided	literature only
Inherited Neuropathy Consortium Ii, University Of Miami	RCV001206561	SCV004174598	uncertain significance	Charcot-Marie-Tooth disease type 4A	2016-01-06	no assertion criteria provided	literature only