Total submissions: 10
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000200426 | SCV000255035 | uncertain significance | Charcot-Marie-Tooth disease type 4A | 2024-01-19 | 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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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. |
Gene |
RCV000416100 | SCV000279436 | uncertain significance | not provided | 2023-08-30 | 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 (Volodarsky et al., 2021); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32376792, 20849849) |
Ce |
RCV000416100 | SCV000493443 | uncertain significance | not provided | 2023-09-01 | criteria provided, single submitter | clinical testing | GDAP1: PM2:Supporting |
Illumina Laboratory Services, |
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, |
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, |
RCV000416100 | SCV001713471 | uncertain significance | not provided | 2021-03-31 | criteria provided, single submitter | clinical testing | |
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, |
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 | 2021-12-10 | criteria provided, single submitter | clinical testing | The p.I186V variant (also known as c.556A>G), located in coding exon 4 of the GDAP1 gene, results from an A to G substitution at nucleotide position 556. The isoleucine at codon 186 is replaced by valine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the supporting evidence, this variant is unlikely to be causative of axonal Charcot-Marie-Tooth disease, type 2K (CMT2K); however, its contribution to the development of the autosomal recessive spectrum of diseases is uncertain. |
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 |