ClinVar Miner

Submissions for variant NM_020549.4(CHAT):c.406G>A (p.Val136Met) (rs201479289)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000331340 SCV000338364 uncertain significance not provided 2015-12-21 criteria provided, single submitter clinical testing
GeneDx RCV000331340 SCV000329253 pathogenic not provided 2017-06-27 criteria provided, single submitter clinical testing The V136M pathogenic variant in the CHAT gene has been previously reported in both compound heterozygous and homozygous patients with congenital myasthenic syndromes (Shen et al., 2011; Arredondo et al., 2015). Functional studies show that the V136M variant lowers protein expression to 50-60% of the level of wild-type CHAT, as well as reduces the overall catalytic efficiency of the enzyme (Shen et al., 2011; Arredondo et al., 2015). The V136M variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. Therefore, we interpret V136M as a pathogenic variant.
Invitae RCV000698479 SCV000827145 likely pathogenic Familial infantile myasthenia 2018-10-09 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 136 of the CHAT protein (p.Val136Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs201479289, ExAC 0.01%). This variant has been observed to be homozygous or in combination with another CHAT variant in individuals affected with congenital myasthenic syndrome (PMID: 21786365, 26080897, 28497657). ClinVar contains an entry for this variant (Variation ID: 279754). Experimental studies have shown that this missense change results in reduced expression of CHAT protein and reduced  catalytic efficiency (PMID: 21786365, 26080897). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare 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.

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