ClinVar Miner

Submissions for variant NM_005677.4(COLQ):c.1354C>T (p.Arg452Cys)

gnomAD frequency: 0.00003  dbSNP: rs368932156
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001068539 SCV001233656 uncertain significance Congenital myasthenic syndrome 5 2022-03-09 criteria provided, single submitter clinical testing This missense change has been observed in individual(s) with clinical features of congenital myasthenic syndrome (PMID: 23553736). 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 have shown that this missense change affects COLQ function (PMID: 23553736). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 861918). This variant is present in population databases (rs368932156, gnomAD 0.02%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 452 of the COLQ protein (p.Arg452Cys).
Revvity Omics, Revvity RCV001068539 SCV003829895 uncertain significance Congenital myasthenic syndrome 5 2019-05-01 criteria provided, single submitter clinical testing
Baylor Genetics RCV001068539 SCV004214439 likely pathogenic Congenital myasthenic syndrome 5 2024-02-18 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004689980 SCV005186120 uncertain significance not specified 2024-05-01 criteria provided, single submitter clinical testing Variant summary: COLQ c.1354C>T (p.Arg452Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.5e-05 in 1614102 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in COLQ causing Congenital Myasthenic Syndrome (2.5e-05 vs 0.0014), allowing no conclusion about variant significance. c.1354C>T has been reported in the literature as a compound heterozygous genotype in individuals affected with Congenital Myasthenic Syndrome (example, Nakata_2013, Cho_2020, Horibe_2023). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (example, Nakata_2013). The most pronounced variant effect results in less than 50% of normal acetylcholinesterase (AChE) activity in-vitro and protein mislocalization. The following publications have been ascertained in the context of this evaluation (PMID: 37238317, 23553736).ClinVar contains an entry for this variant (Variation ID: 861918). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

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