Submissions for variant NM_018972.4(GDAP1):c.556A>G (p.Ile186Val)

gnomAD frequency: 0.00040  dbSNP: rs148508128

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000200426	SCV000255035	uncertain significance	Charcot-Marie-Tooth disease type 4A	2024-12-17	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 186 of the GDAP1 protein (p.Ile186Val). This variant is present in population databases (rs148508128, gnomAD 0.06%). This missense change has been observed in individual(s) with clinical features of Charcot-Marie-Tooth disease (PMID: 32376792). ClinVar contains an entry for this variant (Variation ID: 216707). 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 not expected to disrupt GDAP1 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV000416100	SCV000279436	uncertain significance	not provided	2024-12-03	criteria provided, single submitter	clinical testing	Reported previously as a variant of uncertain significance in two patients with a clinical diagnosis of Charcot-Marie-Tooth disease; however, clinical and segregation information was not provided (PMID: 32376792); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 20849849, 32376792)
CeGaT Center for Human Genetics Tuebingen	RCV000416100	SCV000493443	uncertain significance	not provided	2023-09-01	criteria provided, single submitter	clinical testing	GDAP1: PM2:Supporting
Illumina Laboratory Services, Illumina	RCV001159853	SCV001321596	uncertain significance	Charcot-Marie-Tooth disease recessive intermediate A	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001161257	SCV001323114	uncertain significance	Charcot-Marie-Tooth disease, axonal, with vocal cord paresis, autosomal recessive	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Mayo Clinic Laboratories, Mayo Clinic	RCV000416100	SCV001713471	uncertain significance	not provided	2021-03-31	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000416100	SCV002049066	uncertain significance	not provided	2023-09-11	criteria provided, single submitter	clinical testing	The GDAP1 c.556A>G; p.Ile186Val variant (rs148508128) is reported in the literature in individuals with suspected CMT, but without evidence for pathogenicity (Volodarsky 2021). This variant is reported in ClinVar (Variation ID: 216707) and is found in the non-Finnish European population with an allele frequency of 0.06% (73/129024 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.354). Due to limited information, the clinical significance of the p.Ile186Val variant is uncertain at this time. References: Volodarsky M et al. Comprehensive genetic sequence and copy number analysis for Charcot-Marie-Tooth disease in a Canadian cohort of 2517 patients. J Med Genet. 2021 Apr;58(4):284-288. PMID: 32376792.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000416100	SCV002568161	uncertain significance	not provided	2022-06-01	criteria provided, single submitter	clinical testing	No Applicable ACMG Criteria
Ambry Genetics	RCV002345717	SCV002650013	uncertain significance	Inborn genetic diseases	2023-01-03	criteria provided, single submitter	clinical testing	Unlikely to be causative of GDAP1-related Charcot-Marie-Tooth disease, type 2 (AD) Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002492919	SCV002776018	uncertain significance	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	2021-11-17	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV004998412	SCV005621731	likely benign	not specified	2024-06-27	criteria provided, single submitter	clinical testing