Submissions for variant NM_018972.4(GDAP1):c.487C>T (p.Gln163Ter)

gnomAD frequency: 0.00015  dbSNP: rs104894077

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000204463	SCV000260870	pathogenic	Charcot-Marie-Tooth disease type 4A	2025-01-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln163*) in the GDAP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GDAP1 are known to be pathogenic (PMID: 11743580). This variant is present in population databases (rs104894077, gnomAD 0.05%). This premature translational stop signal has been observed in individual(s) with autosomal recessive Charcot-Marie-Tooth disease (PMID: 11743580, 12601710, 20849849). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4193). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000236485	SCV000292799	pathogenic	not provided	2022-06-06	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 11743580, 31827005, 25525159, 25403865, 12601710, 26257172, 21519004, 26848201, 15805163, 33903021, 33187793, 31589614)
Fulgent Genetics, Fulgent Genetics	RCV000763605	SCV000894451	pathogenic	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	2018-10-31	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000236485	SCV001880593	pathogenic	not provided	2021-02-25	criteria provided, single submitter	clinical testing	This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant segregates with disease in multiple families. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic.
Revvity Omics, Revvity	RCV000236485	SCV002024235	pathogenic	not provided	2024-01-03	criteria provided, single submitter	clinical testing
3billion	RCV000204463	SCV002058858	pathogenic	Charcot-Marie-Tooth disease type 4A	2023-06-20	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense changes are a common disease-causing mechanism. Functional studies provide supporting evidence of the variant having a damaging effect on the gene or gene product (PMID: 20023659). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.76 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.81 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000001051 /PMID: 20023659) and a different missense change at the same codon (p.Arg218Trp / ClinVar ID: VCV000001052 /PMID: 20023659) have been previously reported as pathogenic/likely pathogenic with strong evidence.The variant has been observed in at least two similarly affected unrelated individuals (PMID: 20023659, 30773290). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005055503	SCV005725832	pathogenic	Charcot-Marie-Tooth disease axonal type 2K	2024-11-25	criteria provided, single submitter	clinical testing	Variant summary: GDAP1 c.487C>T (p.Gln163X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 7.6e-05 in 251134 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in GDAP1 causing Charcot-Marie-Tooth disease axonal type 2K, allowing no conclusion about variant significance. c.487C>T has been reported in the literature in multiple individuals affected with Charcot-Marie-Tooth disease (Claramunt_2005). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 15805163). ClinVar contains an entry for this variant (Variation ID: 4193). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000004413	SCV000024586	pathogenic	Neuropathy, axonal, with vocal cord paresis, autosomal recessive	2005-04-01	no assertion criteria provided	literature only
GeneReviews	RCV000031963	SCV000054655	not provided	Charcot-Marie-Tooth disease, axonal, with vocal cord paresis, autosomal recessive		no assertion provided	literature only
Genesis Genome Database	RCV000857207	SCV000999789	uncertain significance	Charcot-Marie-Tooth disease	2019-08-14	no assertion criteria provided	research
Inherited Neuropathy Consortium	RCV000857207	SCV001190053	likely pathogenic	Charcot-Marie-Tooth disease		no assertion criteria provided	provider interpretation
GeneReviews	RCV000857207	SCV001750197	not provided	Charcot-Marie-Tooth disease		no assertion provided	literature only
Clinical Genetics, Academic Medical Center	RCV000236485	SCV001925095	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000236485	SCV001955406	pathogenic	not provided		no assertion criteria provided	clinical testing
Inherited Neuropathy Consortium Ii, University Of Miami	RCV000204463	SCV004174591	uncertain significance	Charcot-Marie-Tooth disease type 4A	2016-01-06	no assertion criteria provided	literature only