Submissions for variant NM_018972.4(GDAP1):c.818G>A (p.Arg273Gln)

dbSNP: rs879254192

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000236133	SCV000293766	likely pathogenic	not provided	2016-01-11	criteria provided, single submitter	clinical testing	The R273Q variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. However, a different amino acid substitution at the same position (R273G) has been previously reported in a patient with CMT4C who had another variant on the opposite allele (Kabzinska et al., 2010). R273Q 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. The R273Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
CeGaT Center for Human Genetics Tuebingen	RCV000236133	SCV000575562	uncertain significance	not provided	2016-11-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001066504	SCV001231517	likely pathogenic	Charcot-Marie-Tooth disease type 4A	2024-09-01	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 273 of the GDAP1 protein (p.Arg273Gln). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with tremor or clinical features of autosomal recessive Charcot-Marie-Tooth disease (PMID: 35531120; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 246285). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GDAP1 protein function with a positive predictive value of 80%. This variant disrupts the p.Arg273 amino acid residue in GDAP1. Other variant(s) that disrupt this residue have been observed in individuals with GDAP1-related conditions (PMID: 20232219), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004526651	SCV005039899	uncertain significance	not specified	2024-03-15	criteria provided, single submitter	clinical testing	Variant summary: GDAP1 c.818G>A (p.Arg273Gln) results in a conservative amino acid change located in the Glutathione S-transferase, C-terminal-like domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251478 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.818G>A has been reported in the literature in an individual with tremor who carried the variant in the homozygous state (Vernetti_GDAP1_Tremor_2022). This report does not provide unequivocal conclusions about association of the variant with Charcot-Marie Disease Type 4A. 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: 24627108, 35531120). ClinVar contains an entry for this variant (Variation ID: 246285). Based on the evidence outlined above, the variant was classified as uncertain significance.
Athena Diagnostics	RCV000236133	SCV005622086	uncertain significance	not provided	2024-12-05	criteria provided, single submitter	clinical testing	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity. (http://gnomad.broadinstitute.org) This variant has been identified in at least one individual with clinical features associated with this gene. Polyphen and MutationTaster predict this amino acid change may be damaging to the protein.
Fulgent Genetics, Fulgent Genetics	RCV005044495	SCV005679126	likely 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	2024-03-13	criteria provided, single submitter	clinical testing