rs556827873
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP3_Moderate
The NM_018972.4(GDAP1):āc.653A>Cā(p.Gln218Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000007 in 1,428,180 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 Uncertain significance (ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q218E) has been classified as Uncertain significance.
Frequency
Consequence
NM_018972.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GDAP1 | NM_018972.4 | c.653A>C | p.Gln218Pro | missense_variant | 5/6 | ENST00000220822.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GDAP1 | ENST00000220822.12 | c.653A>C | p.Gln218Pro | missense_variant | 5/6 | 1 | NM_018972.4 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 30
GnomAD4 exome AF: 7.00e-7 AC: 1AN: 1428180Hom.: 0 Cov.: 27 AF XY: 0.00000140 AC XY: 1AN XY: 712908
GnomAD4 genome ? Cov.: 30
ClinVar
Submissions by phenotype
Charcot-Marie-Tooth disease type 4A Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Molecular Genetics, Royal Melbourne Hospital | Mar 30, 2023 | This sequence change is predicted to replace glutamine with proline at codon 218 of the GDAP1 protein (p.(Gln218Pro)). The glutamine residue is evolutionarily conserved (100 vertebrates, UCSC), and is located in the C-terminal glutathione S-transferase domain. There is a moderate physicochemical difference between glutamine and proline. The variant is absent in a large population cohort (gnomAD v2.1 and v3.1), and has not been reported in the relevant medical literature or databases. Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/6 algorithms). A different pathogenic missense variant at this position with a smaller physicochemical difference (p.Gln218Asp) has been shown to cause autosomal dominant Charcot-Marie-Tooth disease (PMID: 18231710, 26525999, 33477664). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PM5, PM2_Supporting, PP3. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.