Submissions for variant NM_001854.4(COL11A1):c.1245+1G>A

gnomAD frequency: 0.00005  dbSNP: rs766849561

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001780801	SCV002287433	likely pathogenic	not provided	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 8 of the COL11A1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs766849561, gnomAD 0.02%). Disruption of this splice site has been observed in individuals with clinical features of autsomal dominant Stickler syndrome (PMID: 26377240, 32381727, 32578940; Invitae). ClinVar contains an entry for this variant (Variation ID: 1324096). Studies have shown that disruption of this splice site results in skipping of exon 8 (also known as exon 9), but is expected to preserve the integrity of the reading-frame (PMID: 32578940). This variant disrupts a region of the COL11A1 protein in which other variant(s) (p.Phe401Leu) have been observed in individuals with COL11A1-related conditions (PMID: 32756486). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002503269	SCV002816755	likely pathogenic	Intervertebral disc disorder; Marshall syndrome; Stickler syndrome type 2; Fibrochondrogenesis 1; Hearing loss, autosomal dominant 37	2021-07-13	criteria provided, single submitter	clinical testing
GeneDx	RCV001780801	SCV004030613	likely pathogenic	not provided	2023-08-19	criteria provided, single submitter	clinical testing	Reported in one patient from a cohort of patients with short stature and x-ray abnormalities (Zhang et al., 2015); Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); Other splice variants in this gene have been reported in HGMD in association with COL11A1-related disorders (HGMD); This variant is associated with the following publications: (PMID: 26377240, 32381727, 32427345, 32756486)
CeGaT Center for Human Genetics Tuebingen	RCV001780801	SCV004042440	pathogenic	not provided	2023-08-01	criteria provided, single submitter	clinical testing	COL11A1: PVS1:Strong, PM2, PP4:Moderate, PS4:Moderate