Submissions for variant NM_020549.5(CHAT):c.59_60del (p.Glu20fs)

dbSNP: rs531450737

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000697500	SCV000826115	likely benign	Familial infantile myasthenia	2024-01-31	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000729219	SCV000856861	uncertain significance	not provided	2018-05-16	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000697500	SCV001521288	uncertain significance	Familial infantile myasthenia	2019-04-25	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
GeneDx	RCV000729219	SCV002038930	uncertain significance	not provided	2022-11-16	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge
Fulgent Genetics, Fulgent Genetics	RCV000697500	SCV002780918	uncertain significance	Familial infantile myasthenia	2022-05-03	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000697500	SCV004235042	uncertain significance	Familial infantile myasthenia	2023-07-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987671	SCV004803627	uncertain significance	not specified	2024-01-22	criteria provided, single submitter	clinical testing	Variant summary: CHAT c.59_60delAG (p.Glu20GlyfsX60) located in the coding exon 1 of the longest CHAT gene transcript, results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. However, this exon is not expressed in multiple alternate CHAT transcripts to include NM_020986, where it is annotated as CHAT NM_020986.4: c.-69+1046_-69+1047delAG in the non-coding 5' UTR region of the CHAT gene. The variant allele was found at a frequency of 0.0003 in 147486 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CHAT causing Congenital Myasthenic Syndrome (0.0003 vs 0.00079), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.59_60delAG in individuals affected with Congenital Myasthenic Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 575316). Based on the evidence outlined above, the variant was classified as uncertain significance.