Submissions for variant NM_020549.5(CHAT):c.406G>A (p.Val136Met)

gnomAD frequency: 0.00011  dbSNP: rs201479289

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000331340	SCV000329253	pathogenic	not provided	2022-04-26	criteria provided, single submitter	clinical testing	Published functional studies demonstrate decreased protein expression, as well as reduced catalytic efficiency of the enzyme (Shen et al., 2011; Arredondo et al., 2015); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28497657, 29783273, 31192527, 31980526, 21786365, 26080897, 29759072, 30609409, 34426522, 34557490, 30458023)
Eurofins Ntd Llc (ga)	RCV000331340	SCV000338364	uncertain significance	not provided	2015-12-21	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000606672	SCV000712088	likely pathogenic	Congenital myasthenic syndrome	2016-05-10	criteria provided, single submitter	clinical testing	The p.Val54Met variant in CHAT has been reported in four patients with congenita l myasthenic syndrome with episodic apnea (three compound heterozygotes and one homozygote) (Shen 2011, Arredondo 2015). This variant has also been identified i n 5/118276 of chromosomes by the Exome Aggregation Consortium (ExAC, http://exac .broadinstitute.org; dbSNP rs201479289). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a rece ssive carrier frequency. In vitro functional studies provide some evidence that the p.Val54Met variant may impact protein function (Shen 2011, Arredondo 2015). However, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its cli nical significance, the p.Val54Met variant is likely pathogenic.
Invitae	RCV000698479	SCV000827145	pathogenic	Familial infantile myasthenia	2023-11-05	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 136 of the CHAT protein (p.Val136Met). This variant is present in population databases (rs201479289, gnomAD 0.02%). This missense change has been observed in individual(s) with congenital myasthenic syndrome (PMID: 21786365, 26080897, 28497657; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 279754). 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: 21786365, 26080897). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000698479	SCV002022530	likely pathogenic	Familial infantile myasthenia	2023-07-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000606672	SCV003801156	pathogenic	Congenital myasthenic syndrome	2023-01-24	criteria provided, single submitter	clinical testing	Variant summary: CHAT c.406G>A (p.Val136Met) results in a conservative amino acid change located in the Choline/carnitine acyltransferase domain (IPR039551) of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 250372 control chromosomes (gnomAD and publication data). This frequency is not significantly higher than expected for a pathogenic variant in CHAT causing Congenital Myasthenic Syndrome (4e-05 vs 0.00079), allowing no conclusion about variant significance. c.406G>A has been reported in the literature in multiple individuals affected with Congenital Myasthenic Syndrome, including at least one homozygote (Shen_2011, Abicht_2012, Arredondo_2015). These data indicate that the variant is very likely to be associated with disease. Functional studies report this variant results in reducing protein expression level and catalytic efficiency of the enzyme (Shen_2011, Arredondo_2015). Five ClinVar submitters (evaluation after 2014) cite this variant as pathogenic (n=2), likely pathogenic (n=2) and uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000698479	SCV004215796	pathogenic	Familial infantile myasthenia	2024-03-20	criteria provided, single submitter	clinical testing