rs372760913
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong
The NM_020549.5(CHAT):c.1669G>A(p.Ala557Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000644 in 1,613,868 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 (★★). Synonymous variant affecting the same amino acid position (i.e. A557A) has been classified as Likely benign.
Frequency
Consequence
NM_020549.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CHAT | NM_020549.5 | c.1669G>A | p.Ala557Thr | missense_variant | 12/15 | ENST00000337653.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CHAT | ENST00000337653.7 | c.1669G>A | p.Ala557Thr | missense_variant | 12/15 | 1 | NM_020549.5 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000395 AC: 6AN: 152050Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000517 AC: 13AN: 251264Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135882
GnomAD4 exome AF: 0.0000670 AC: 98AN: 1461818Hom.: 0 Cov.: 37 AF XY: 0.0000701 AC XY: 51AN XY: 727216
GnomAD4 genome ? AF: 0.0000395 AC: 6AN: 152050Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74246
ClinVar
Submissions by phenotype
Familial infantile myasthenia Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 29, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 10, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 557 of the CHAT protein (p.Ala557Thr). This variant is present in population databases (rs372760913, gnomAD 0.009%). This missense change has been observed in individuals with congenital myasthenic syndrome (PMID: 19520274, 29189923; Invitae). ClinVar contains an entry for this variant (Variation ID: 461452). 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 expected to disrupt CHAT protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects CHAT function (PMID: 21786365). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 27, 2022 | Published functional studies demonstrate a damaging effect, as the A557T variant demonstrates reduced expression, low catalytic rate, and an extremely low affinity for acetyl-CoA and choline in comparison to wild-type (PMID: 21786365); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19520274, 21786365, 29189923, 29783273, 26080897, 33650116, Kong 2022 [Poster], 34431804) - |
Congenital myasthenic syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 20, 2023 | Variant summary: CHAT c.1669G>A (p.Ala557Thr) 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 5.2e-05 in 251264 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in CHAT causing Congenital Myasthenic Syndrome (5.2e-05 vs 0.00079), allowing no conclusion about variant significance. c.1669G>A has been reported in the literature in multiple individuals affected with Congenital Myasthenic Syndrome (e.g., Mallory_2009, Shen_2011). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in reduced expression and catalytic efficiency (e.g., Shen_2011). The following publications have been ascertained in the context of this evaluation (PMID: 19520274, 21786365). Three submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely 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