Submissions for variant NM_005677.4(COLQ):c.1A>G (p.Met1Val)

gnomAD frequency: 0.00001  dbSNP: rs754147251

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002046334	SCV002316170	uncertain significance	Congenital myasthenic syndrome 5	2021-09-26	criteria provided, single submitter	clinical testing	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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals affected with COLQ-related conditions. This variant is present in population databases (rs754147251, ExAC 0.006%). This sequence change affects the initiator methionine of the COLQ mRNA. The next in-frame methionine is located at codon 7.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002222751	SCV002500098	uncertain significance	not specified	2022-03-04	criteria provided, single submitter	clinical testing	Variant summary: COLQ c.1A>G (p.Met1?) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. An alternative downstream in-frame start codon (Met7) is located in the encoded protein. An activation of potential downstream translation initiation site would result in a shortened protein missing the first 6 amino acids from the protein sequence. To our knowledge no other pathogenic variants has been reported upstream of this alternate codon. Two of three in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251430 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1A>G in individuals affected with Congenital Myasthenic Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.