8-74360173-T-G
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PM5PP3_ModeratePP5_Very_Strong
The NM_018972.4(GDAP1):c.347T>G(p.Met116Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000434 in 1,613,594 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M116T) has been classified as Pathogenic.
Frequency
Consequence
NM_018972.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152226Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251466Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135906
GnomAD4 exome AF: 0.00000411 AC: 6AN: 1461368Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 727046
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152226Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74366
ClinVar
Submissions by phenotype
not provided Pathogenic:2
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Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 38428336, 16607474, 32376792, 28837237, 25429913, 38374194, 36790232, 15377708, 20685671, 20849849, 23628762, 21965300) -
Charcot-Marie-Tooth disease type 4A Pathogenic:1Other:1
This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 116 of the GDAP1 protein (p.Met116Arg). This variant is present in population databases (rs281865060, gnomAD 0.003%). This missense change has been observed in individuals with autosomal recessive Charcot-Marie-Tooth disease (PMID: 15377708, 25429913). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 38411). 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%. Experimental studies have shown that this missense change does not substantially affect GDAP1 function (PMID: 21965300). For these reasons, this variant has been classified as Pathogenic. -
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Charcot-Marie-Tooth disease Uncertain:1Other:1
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Peripheral neuropathy Pathogenic:1
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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 Pathogenic:1
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Charcot-Marie-Tooth disease axonal type 2K Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at