Submissions for variant NM_018972.4(GDAP1):c.786del (p.Phe263fs)

dbSNP: rs1060500978

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000456890	SCV000544592	pathogenic	Charcot-Marie-Tooth disease type 4A	2023-06-02	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the GDAP1 protein in which other variant(s) (p.Arg341Glnfs*12) have been determined to be pathogenic (PMID: 25614874). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 406136). This premature translational stop signal has been observed in individuals with autosomal recessive Charcot-Marie-Tooth disease (PMID: 12499475). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Phe263Leufs*22) in the GDAP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 96 amino acid(s) of the GDAP1 protein.
GeneDx	RCV000479637	SCV000565035	likely pathogenic	not provided	2018-08-23	criteria provided, single submitter	clinical testing	The c.786delG variant in the GDAP1 gene has been reported previously in the homozygous state in multiple affected siblings from two unrelated families segregating an autosomal recessive form of Charcot-Marie-Tooth syndrome; all tested family members who were heterozygous for the c.786delG variant were unaffected (Nelis et al., 2002). The c.786delG variant causes a frameshift starting with codon Phenylalanine 263, changes this amino acid to a Leucine residue, and creates a premature Stop codon at position 22 of the new reading frame, denoted p.Phe263LeufsX22. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.786delG variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.786delG as a likely pathogenic variant; however, the possibility it may be a rare benign variant cannot be completely excluded.
CeGaT Center for Human Genetics Tuebingen	RCV000479637	SCV001249600	pathogenic	not provided	2017-08-01	criteria provided, single submitter	clinical testing
CMT Laboratory, Bogazici University	RCV000456890	SCV001548301	pathogenic	Charcot-Marie-Tooth disease type 4A	2020-12-01	criteria provided, single submitter	clinical testing
3billion	RCV001809345	SCV002059082	pathogenic	Charcot-Marie-Tooth disease recessive intermediate A	2022-01-03	criteria provided, single submitter	clinical testing	Frameshift: predicted to result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region (PVS1_S). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000406136, PMID:12499475). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
MGZ Medical Genetics Center	RCV000456890	SCV002580503	pathogenic	Charcot-Marie-Tooth disease type 4A	2021-10-21	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001809345	SCV003922261	pathogenic	Charcot-Marie-Tooth disease recessive intermediate A	2023-05-02	criteria provided, single submitter	curation	The homozygous p.Phe263LeufsTer22 variant in GDAP1 was identified by our study in one individual with peripheral neuropathy. The p.Phe263LeufsTer22 variant in GDAP1 has been previously reported in 9 unrelated individuals with Charcot-Marie-Tooth disease type 4A (PMID: 34476298, PMID: 30373780, PMID: 34169998, PMID: 12499475, ClinVar SCV002059082.1) and segregated with disease in 9 affected relatives from four families (PMID: 12499475, PMID: 34476298). These 9 previously reported unrelated individuals were homozygotes, which increases the likelihood that the p.Phe263LeufsTer22 variant in GDAP1 is pathogenic (PMID: 34476298, PMID: 30373780, PMID: 34169998, PMID: 12499475, ClinVar SCV002059082.1). This variant has also been reported in ClinVar (Variation ID: 406136) and has been interpreted as pathogenic or likely pathogenic by multiple submitters. This variant was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 263 and leads to a premature termination codon 22 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. This termination codon occurs within the terminal 50 bases of the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Loss of function of the GDAP1 gene is an established disease mechanism in autosomal recessive Charcot-Marie-Tooth disease type 4A. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Charcot-Marie-Tooth disease type 4A. ACMG/AMP Criteria applied: PVS1_Strong, PM2_Supporting, PM3, PP1_Strong (Richards 2015).
Inherited Neuropathy Consortium	RCV000789157	SCV000928509	uncertain significance	Charcot-Marie-Tooth disease		no assertion criteria provided	literature only
Genesis Genome Database	RCV000789157	SCV000999793	uncertain significance	Charcot-Marie-Tooth disease	2019-08-14	no assertion criteria provided	research
Inherited Neuropathy Consortium Ii, University Of Miami	RCV000456890	SCV004174583	uncertain significance	Charcot-Marie-Tooth disease type 4A	2016-01-06	no assertion criteria provided	literature only