Submissions for variant NM_018972.4(GDAP1):c.786del (p.Phe263fs) (rs1060500978)

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000456890	SCV000544592	pathogenic	Charcot-Marie-Tooth disease, type 4A	2019-05-17	criteria provided, single submitter	clinical testing	This sequence change deletes 1 nucleotide in exon 6 of the GDAP1 mRNA (c.786delG), causing a frameshift at codon 263. This creates a premature translational stop signal in the last exon of the GDAP1 mRNA (p.Phe263Leufs*22). While this is not anticipated to result in nonsense mediated decay, it is expected to result in a truncated GDAP1 protein. This variant has been previously reported to segregate with disease in a single family affected with autosomal recessive Charcot-Marie-Tooth disease (PMID: 12499475). A different truncation downstream of this variant (p.Arg341Glnfs*12) has been determined to be pathogenic (PMID: 25614874). This suggests that deletion of this region of the GDAP1 protein is causative of disease. For these reasons, this variant has been classified as Pathogenic.
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 Praxis fuer Humangenetik Tuebingen	RCV000479637	SCV001249600	pathogenic	not provided	2017-08-01	criteria provided, single submitter	clinical testing
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