rs756121249
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_018972.4(GDAP1):c.109T>A(p.Ser37Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000488 in 1,434,190 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S37S) has been classified as Likely benign.
Frequency
Consequence
NM_018972.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GDAP1 | NM_018972.4 | c.109T>A | p.Ser37Thr | missense_variant | 1/6 | ENST00000220822.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GDAP1 | ENST00000220822.12 | c.109T>A | p.Ser37Thr | missense_variant | 1/6 | 1 | NM_018972.4 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 34
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251336Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135874
GnomAD4 exome AF: 0.00000488 AC: 7AN: 1434190Hom.: 0 Cov.: 27 AF XY: 0.00000140 AC XY: 1AN XY: 715138
GnomAD4 genome ? Cov.: 34
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 28, 2017 | A variant that is likely pathogenic has been identified in the GDAP1 gene. The S37T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The S37T variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a conserved position predicted to be within the GST N-terminal domain. Missense variants at other residues in the GST domain have been reported in Human Gene Mutation Database in association with GDAP1-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. However, the S37T variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 07, 2017 | - - |
Charcot-Marie-Tooth disease type 4A Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 30, 2023 | This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 37 of the GDAP1 protein (p.Ser37Thr). This variant is present in population databases (rs756121249, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with GDAP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 426898). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at