ClinVar Miner

Submissions for variant NM_020549.4(CHAT):c.605T>G (p.Met202Arg) (rs376808313)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000494066 SCV000582780 pathogenic not provided 2019-01-09 criteria provided, single submitter clinical testing The M202R pathogenic variant in the CHAT gene has been reported previously with a pathogenic variant on the opposite allele (in trans) in an individual with myasthenia (Shen et al., 2011). The M202R variant is observed in 28/24,004 (0.12%) alleles from individuals of African background in large population cohorts, with no homozygous individuals observed (Lek et al., 2016). The M202R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This variant occurs at a residue that is in a coil region connecting the binding to the catalytic domain (Shen et al., 2011). Functional studies showed that the M202R variant has severe kinetic effects on the CHAT protein, significantly reducing its catalytic efficiency (Shen et al., 2011). The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014). We interpret M202R as a pathogenic variant.
Invitae RCV000813390 SCV000953749 uncertain significance Familial infantile myasthenia 2018-10-05 criteria provided, single submitter clinical testing This sequence change replaces methionine with arginine at codon 202 of the CHAT protein (p.Met202Arg). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and arginine. This variant is present in population databases (rs376808313, ExAC 0.08%). This variant has been observed on the opposite chromosome (in trans) from a likely pathogenic variant in an individual affected with congenital myasthenic syndrome (PMID: 21786365). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 430062). Experimental studies have shown that this missense change results in impaired enzyme kinetics (PMID: 21786365). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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