ClinVar Miner

Submissions for variant NM_020549.5(CHAT):c.1669G>A (p.Ala557Thr)

gnomAD frequency: 0.00004  dbSNP: rs372760913
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000529557 SCV000634120 pathogenic Familial infantile myasthenia 2024-01-29 criteria provided, single submitter clinical testing 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.
GeneDx RCV001557756 SCV001779573 pathogenic not provided 2022-07-27 criteria provided, single submitter clinical testing 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)
Revvity Omics, Revvity RCV000529557 SCV002022528 likely pathogenic Familial infantile myasthenia 2019-08-29 criteria provided, single submitter clinical testing
Baylor Genetics RCV000529557 SCV004215802 pathogenic Familial infantile myasthenia 2023-10-10 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003479154 SCV004222978 pathogenic Congenital myasthenic syndrome 2023-11-20 criteria provided, single submitter clinical testing 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.

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