rs764497513
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM5PP3_ModeratePP5
The NM_020549.5(CHAT):c.620G>A(p.Arg207His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,613,648 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R207G) has been classified as Likely pathogenic.
Frequency
Consequence
NM_020549.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CHAT | NM_020549.5 | c.620G>A | p.Arg207His | missense_variant | 4/15 | ENST00000337653.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CHAT | ENST00000337653.7 | c.620G>A | p.Arg207His | missense_variant | 4/15 | 1 | NM_020549.5 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152122Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251416Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135888
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461526Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 727088
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152122Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74304
ClinVar
Submissions by phenotype
Familial infantile myasthenia Pathogenic:3Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 11, 2023 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 207 of the CHAT protein (p.Arg207His). This variant is present in population databases (rs764497513, gnomAD 0.007%). This missense change has been observed in individuals with congenital myasthenic syndrome (PMID: 26080897). ClinVar contains an entry for this variant (Variation ID: 289944). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CHAT protein function. Experimental studies have shown that this missense change affects CHAT function (PMID: 26080897). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Mar 05, 2018 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 10, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Nov 12, 2015 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 16, 2016 | - - |
Congenital myasthenic syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 14, 2023 | Variant summary: CHAT c.620G>A (p.Arg207His) results in a non-conservative amino acid change located in the Choline/carnitine acyltransferase domain (IPR039551) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251416 control chromosomes (gnomAD). c.620G>A has been reported in the literature in individuals affected with Congenital Myasthenic Syndrome (Arredondo_2016). These data indicate that the variant is likely to be associated with disease. In transfected HEK293 cells, the variant had 81% expression levels as compared to wild-type, but only 3% catalytic efficiency (Arredondo_2016). Four ClinVar submitters have assessed the variant since 2014: one classified the variant as uncertain significance, two as likely pathogenic, and one as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at