Submissions for variant NM_001854.4(COL11A1):c.3276+5G>A

dbSNP: rs2101406246

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002045357	SCV002288449	uncertain significance	not provided	2022-11-22	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. 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 may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 1503133). This variant has not been reported in the literature in individuals affected with COL11A1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 42 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.
GeneDx	RCV002045357	SCV004022745	likely pathogenic	not provided	2023-07-26	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed in large population cohorts (gnomAD); Intronic +5 splice site variant in a gene for which loss of function is a known mechanism of disease, and both splice predictors and evolutionary conservation support a deleterious effect, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Damages or destroys the splice donor site in intron 42, and is expected to cause abnormal gene splicing; if the splice outcome is exon skip, the loss of the encoded residues in the triple helical region is expected to disrupt normal protein folding and function (HGMD; Acke et al., 2014); This variant is associated with the following publications: (PMID: 25240749)
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV003453951	SCV004190131	uncertain significance	Stickler syndrome type 2	2023-12-21	criteria provided, single submitter	curation	The c.3276+5G>A variant in COL11A1 was identified by our study in 2 family members with Stickler syndrome type 2. This variant was absent from large population studies. 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. An additional likely pathogenic variant, predicted to induce the same splicing effect as this variant, has been reported in ClinVar as being associated with Stickler syndrome type 2, supporting that the c.3276+5G>A variant may be pathogenic (Variation ID: 1698769). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PP3, PM2_supporting, PS1_supporting (Richards 2015).