Submissions for variant NM_005677.4(COLQ):c.1289A>C (p.Tyr430Ser)

gnomAD frequency: 0.00005  dbSNP: rs121908923

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000007033	SCV001579178	pathogenic	Congenital myasthenic syndrome 5	2023-02-10	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with serine, which is neutral and polar, at codon 430 of the COLQ protein (p.Tyr430Ser). This variant is present in population databases (rs121908923, gnomAD 0.02%). This missense change has been observed in individuals with congenital myasthenic syndrome (PMID: 9758617, 29054425). It has also been observed to segregate with disease in related individuals. This variant is also known as Y431S. ClinVar contains an entry for this variant (Variation ID: 6654). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt COLQ protein function. Experimental studies have shown that this missense change affects COLQ function (PMID: 15159418). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000007033	SCV002019704	pathogenic	Congenital myasthenic syndrome 5	2019-04-30	criteria provided, single submitter	clinical testing
DASA	RCV001813737	SCV002061294	pathogenic	Myasthenic syndrome, slow-channel congenital	2022-01-05	criteria provided, single submitter	clinical testing	The c.1289A>C;p.(Tyr430Ser) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 6654; PMID: 29054425) - PS4.The variant is present at low allele frequencies population databases (rs121908923– gnomAD 0.0004608%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Tyr430Ser) was detected in trans with a pathogenic variant (PMID: 29054425) - PM3_strong. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic.
Baylor Genetics	RCV000007033	SCV004214440	pathogenic	Congenital myasthenic syndrome 5	2024-03-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004526590	SCV005039838	pathogenic	Congenital myasthenic syndrome	2024-03-18	criteria provided, single submitter	clinical testing	Variant summary: COLQ c.1289A>C (p.Tyr430Ser) 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 4.1e-05 in 245298 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in COLQ causing Congenital Myasthenic Syndrome (4.1e-05 vs 0.0014), allowing no conclusion about variant significance. c.1289A>C has been reported in the literature in multiple homozygous individuals affected with Congenital Myasthenic Syndrome (e.g. Abicht_2012). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 22678886). ClinVar contains an entry for this variant (Variation ID: 6654). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000007033	SCV000027229	pathogenic	Congenital myasthenic syndrome 5	1998-10-01	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004757099	SCV005347547	pathogenic	COLQ-related disorder	2024-09-26	no assertion criteria provided	clinical testing	The COLQ c.1289A>C variant is predicted to result in the amino acid substitution p.Tyr430Ser. This variant has been reported in the homozygous state in several siblings in a large family to be causative for congenital myasthenic syndrome (Donger et al. 1998. PubMed ID: 9758617). This variant has also been reported in the compound heterozygous state in several additional individuals with congenital myasthenic syndrome (Servais et al. 2012. PubMed ID: 23108489; Natera-de Benito et al. 2017. PubMed ID: 29054425). This variant is reported in 0.017% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic.