Submissions for variant NM_005677.4(COLQ):c.219+1G>C

gnomAD frequency: 0.00001  dbSNP: rs149020371

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Mendelics	RCV000987125	SCV001136331	pathogenic	Congenital myasthenic syndrome 5	2019-05-28	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000987125	SCV002019706	pathogenic	Congenital myasthenic syndrome 5	2020-02-12	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000987125	SCV002129691	pathogenic	Congenital myasthenic syndrome 5	2023-06-07	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 801940). This variant is also known as IVS2+1G>C. Disruption of this splice site has been observed in individuals with congenital myasthenic syndrome (PMID: 18180250, 22088788). This variant is present in population databases (rs149020371, gnomAD 0.006%). This sequence change affects a donor splice site in intron 2 of the COLQ gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in COLQ are known to be pathogenic (PMID: 22678886).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002307647	SCV002600411	pathogenic	Congenital myasthenic syndrome	2022-10-10	criteria provided, single submitter	clinical testing	Variant summary: COLQ c.219+1G>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing by abolishment of 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.6e-05 in 251438 control chromosomes. c.219+1G>C has been reported in the literature as a homozygous and heterozygous genotype in multiple individuals with clinically diagnosed Congenital Myasthenic Syndrome (example: Estepha_2022, Mihaylova_2008 and Wargon_2012 etc.). 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. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000987125	SCV003922105	pathogenic	Congenital myasthenic syndrome 5	2023-05-02	criteria provided, single submitter	curation	The homozygous c.219+1G>C variant in COLQ was identified by our study in two siblings with congenital myasthenic syndrome (PMID: 34749429). The c.219+1G>C variant in COLQ has been previously reported in four unrelated individuals with congenital myasthenic syndrome 5 (PMID: 18180250, PMID: 34749429, PMID: 22088788), segregated with disease in four affected relatives from two families (PMID: 22088788, PMID: 34749429), but has been identified in 0.006% (2/34586) Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs149020371). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 801940) and has been interpreted as pathogenic by Mendelics, Invitae, and PerkinElmer Genomics. Of the four unrelated affected individuals, two were homozygotes (PMID: 18180250, PMID: 34749429) one was a reported compound heterozygote who carried a pathogenic variant in unknown phase (PMID: 34749429, ClinVar Variation ID: 468343), and one was a compound heterozygote who carried a variant of uncertain significance in trans (PMID: 22088788, ClinVar Variation ID: 536239), which increases the likelihood that the c.219+1G>C variant is pathogenic. This variant is located in the 5' splice region. Computational tools do suggest an impact to splicing. However, this information is not predictive enough to determine pathogenicity. Loss of function of the COLQ gene is an established disease mechanism in autosomal recessive congenital myasthenic syndrome 5. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive congenital myasthenic syndrome 5. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PM3 (Richards 2015).
GeneDx	RCV003328641	SCV004035832	pathogenic	not provided	2023-03-16	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Reported in two siblings with congenital myasthenia who had a second COLQ variant (Wargon et al., 2012); This variant is associated with the following publications: (PMID: 25525159, 34749429, 18180250, 22088788)
Baylor Genetics	RCV000987125	SCV004214455	pathogenic	Congenital myasthenic syndrome 5	2023-12-04	criteria provided, single submitter	clinical testing