Submissions for variant NM_020549.5(CHAT):c.605T>G (p.Met202Arg)

gnomAD frequency: 0.00045  dbSNP: rs376808313

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000494066	SCV000582780	pathogenic	not provided	2021-11-12	criteria provided, single submitter	clinical testing	Published functional studies demonstrate severe kinetic effects on the CHAT protein, significantly reducing its catalytic efficiency (Shen et al., 2011); 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: 25792100, 26080897, 32019516, 21786365)
Invitae	RCV000813390	SCV000953749	pathogenic	Familial infantile myasthenia	2024-01-10	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 202 of the CHAT protein (p.Met202Arg). This variant is present in population databases (rs376808313, gnomAD 0.1%). This missense change has been observed in individual(s) with congenital myasthenic syndrome (PMID: 21786365; 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: 430062). 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). For these reasons, this variant has been classified as Pathogenic.
3billion	RCV000813390	SCV002058166	uncertain significance	Familial infantile myasthenia	2022-01-03	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000103, PM2_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.94, PP3_P). A missense variant is a common mechanism associated with Myasthenic syndrome (PP2_P). Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002469176	SCV002766422	likely pathogenic	Congenital myasthenic syndrome	2022-11-07	criteria provided, single submitter	clinical testing	Variant summary: CHAT c.605T>G (p.Met202Arg) results in a non-conservative amino acid change located in the Choline/carnitine acyltransferase domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. This variant alters a highly conserved nucleotide located in the active-site tunnel of the protein (Shen_2011). The variant allele was found at a frequency of 6e-05 in 251406 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CHAT causing Congenital Myasthenic Syndrome (6e-05 vs 0.00079), allowing no conclusion about variant significance. c.605T>G has been reported in the literature in an individual affected with ChAT deficiency (Shen_2011). Additionally, functional assessment of the recombinantly-expressed mutant showed the variant to drastically reduce the catalytic efficiency of the protein (Shen_2011). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Two submitters classified as pathogenic while one classified as VUS. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Genetics and Molecular Pathology, SA Pathology	RCV000813390	SCV004175199	likely pathogenic	Familial infantile myasthenia	2023-01-17	criteria provided, single submitter	clinical testing	The CHAT c.605T>G variant is classified as a LIKELY PATHOGENIC (PM2, PS3_supporting, PS4_supporting, PM1_supporting, PP3) This variant is a single nucleotide change in exon 4/15 of the CHAT gene, which is predicted to change the amino acid methionine at position 202 in the protein to arginine. The variant is located in the active site tunnel of the protein domain of the CHAT gene, causing severe kinetic effects (PMID: 21786365) (PM1_supporting). The variant has been reported in multiple individuals with congenital myasthenic syndrome in both homozygous or compound heterozygous state (PMID: 21786365, 33820833) (PS4_supporting). Functional studies have demonstrated that this variant had a severe kinetic effects on the CHAT protein, significantly reducing its catalytic efficiency (PMID: 21786365) (PS3_supporting). The variant is in dbSNP (rs376808313) but has been reported in population databases at a low frequency for an autosomal recessive disease gene (gnomAD (43/152094, 0 homozygotes) (PM2). The vriant has been reported in ClinVar (Variation ID: #430062) and HGMD (Accession no.: CM119376) as pathogenic/likely pathogenic or disease causing. Computational predictions support deleterious effect on the gene or gene product (PP3).
Baylor Genetics	RCV000813390	SCV004215804	likely pathogenic	Familial infantile myasthenia	2024-02-20	criteria provided, single submitter	clinical testing