Submissions for variant NM_001854.4(COL11A1):c.1899+3A>G

gnomAD frequency: 0.00006  dbSNP: rs374676938

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000312205	SCV000346514	uncertain significance	Stickler syndrome type 2	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000262771	SCV000346516	uncertain significance	Fibrochondrogenesis 1	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae	RCV001373961	SCV001570709	uncertain significance	not provided	2023-10-03	criteria provided, single submitter	clinical testing	This sequence change falls in intron 19 of the COL11A1 gene. It does not directly change the encoded amino acid sequence of the COL11A1 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs374676938, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with COL11A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 291528). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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.
GeneDx	RCV001373961	SCV002540498	uncertain significance	not provided	2023-08-08	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this variant does not alter splicing; Has not been previously published as pathogenic or benign to our knowledge
PreventionGenetics, part of Exact Sciences	RCV003417929	SCV004118539	uncertain significance	COL11A1-related condition	2023-08-11	criteria provided, single submitter	clinical testing	The COL11A1 c.1899+3A>G variant is predicted to interfere with splicing. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.015% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-103470161-T-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Revvity Omics, Revvity	RCV001373961	SCV004235361	uncertain significance	not provided	2023-06-14	criteria provided, single submitter	clinical testing