Submissions for variant NM_018972.4(GDAP1):c.767A>G (p.His256Arg) (rs1476856429)

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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000757324	SCV000885503	pathogenic	not provided	2018-02-22	criteria provided, single submitter	clinical testing	The GDAP1 c.767A>G; p.His256Arg variant is reported in the literature in the homozygous or compound heterozygous state in at least six individuals affected with CMT type 2 and was shown to segregate with the disease in at least four of the affected families (Chung 2011, Fu 2017, Lin 2011, Zhang 2004). This variant is listed in the genome Aggregation Database (gnomAD) with an East Asian population frequency of 0.02% (identified on 4 out of 18,868 chromosomes). The histidine at position 256 is highly conserved, considering 12 species, and computational analyses of the effects of the p.His256Arg variant on protein structure and function make conflicting predictions (SIFT: tolerated, PolyPhen-2: probably damaging). Based on the available information, the p.His256Arg variant is likely to be pathogenic.
Inherited Neuropathy Consortium	RCV000789787	SCV000929171	uncertain significance	Charcot-Marie-Tooth disease		no assertion criteria provided	literature only
Invitae	RCV000820420	SCV000961131	pathogenic	Charcot-Marie-Tooth disease, type 4A	2018-08-14	criteria provided, single submitter	clinical testing	This sequence change replaces histidine with arginine at codon 256 of the GDAP1 protein (p.His256Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in either the homozygous or compound heterozygous state in individuals affected with Charcot-Marie-Tooth (CMT) disease and has been observed to segregate with CMT in several families (PMID: 28495047, 22206013, 21692914, 15192818, 29372391). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.

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