rs148508128
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate
The NM_018972.4(GDAP1):āc.556A>Gā(p.Ile186Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000755 in 1,598,174 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I186T) has been classified as Uncertain significance.
Frequency
Consequence
NM_018972.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GDAP1 | NM_018972.4 | c.556A>G | p.Ile186Val | missense_variant | 4/6 | ENST00000220822.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GDAP1 | ENST00000220822.12 | c.556A>G | p.Ile186Val | missense_variant | 4/6 | 1 | NM_018972.4 | P3 |
Frequencies
GnomAD3 genomes AF: 0.000407 AC: 62AN: 152250Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000332 AC: 83AN: 249790Hom.: 0 AF XY: 0.000362 AC XY: 49AN XY: 135210
GnomAD4 exome AF: 0.000792 AC: 1145AN: 1445806Hom.: 1 Cov.: 28 AF XY: 0.000780 AC XY: 562AN XY: 720302
GnomAD4 genome AF: 0.000407 AC: 62AN: 152368Hom.: 0 Cov.: 33 AF XY: 0.000376 AC XY: 28AN XY: 74506
ClinVar
Submissions by phenotype
not provided Uncertain:5
Uncertain significance, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Jun 01, 2022 | No Applicable ACMG Criteria - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Mar 31, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 30, 2023 | 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) - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 11, 2023 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2023 | GDAP1: PM2:Supporting - |
Charcot-Marie-Tooth disease recessive intermediate A Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | 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. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 03, 2023 | 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. - |
Charcot-Marie-Tooth disease type 4A Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 19, 2024 | 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. - |
Charcot-Marie-Tooth disease, axonal, with vocal cord paresis, autosomal recessive Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | 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. - |
Charcot-Marie-Tooth disease recessive intermediate A;C1842983:Charcot-Marie-Tooth disease axonal type 2K;C1843183:Charcot-Marie-Tooth disease, axonal, with vocal cord paresis, autosomal recessive;C1859198:Charcot-Marie-Tooth disease type 4A Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Nov 17, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at