Submissions for variant NM_001854.4(COL11A1):c.1630-2del

dbSNP: rs1057517989

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000413570	SCV000491292	pathogenic	not provided	2022-12-21	criteria provided, single submitter	clinical testing	Destroys the canonical splice acceptor site in intron 14, and is expected to cause abnormal gene splicing; Not observed in large population cohorts (gnomAD); Using fibroblast cDNA derived from patients harboring this variant, Martin et al. (1999) reported this variant results in the skipping of exon 15; the loss of the encoded residues is in the triple helical region and is expected to disrupt normal protein folding and function, and this is an established mechanism of disease (HGMD; Acke et al., 2014); Deletions involving coding exons in this gene are frequently reported as pathogenic, regardless of frame prediction (HGMD); This variant is associated with the following publications: (PMID: 34680973, 34758253, 10486316, 15286167, 20513134, 25240749, 29453956, 28000701, 10573014)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001174947	SCV001338405	pathogenic	Stickler syndrome	2020-02-07	criteria provided, single submitter	clinical testing	Variant summary: COL11A1 c.1630-2delA 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: Four predict that the variant abolishes a 3 acceptor site. This was further supported by a functional study where the authors have shown that this deletion altered the 3 acceptor splice site of the preceding intron leading to skipping of the 54bp exon from the mRNA (Martin_1999). The variant was absent in 250924 control chromosomes (gnomAD). c.1630-2delA has been reported in the literature in multiple individuals affected with Stickler syndrome (examples- Acke_2014, Martin_1999, Richards_2010) as well as in a patient with overlapping Marshall and Stickler syndrome phenotype (Annunen_1999). These data indicate that the variant is very likely to be associated with disease. One ClinVar submitter (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000413570	SCV002228664	pathogenic	not provided	2024-12-02	criteria provided, single submitter	clinical testing	This sequence change affects a splice site in intron 14 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 not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with autosomal dominant Stickler syndrome (PMID: 10573014). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 372792). Studies have shown that disruption of this splice site results in skipping of exon 15, but is expected to preserve the integrity of the reading-frame (PMID: 10573014). For these reasons, this variant has been classified as Pathogenic.
3billion, Medical Genetics	RCV001542539	SCV002318693	pathogenic	Stickler syndrome type 2	2022-03-22	criteria provided, single submitter	clinical testing	Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant.It is not observed in the gnomAD v2.1.1 dataset. The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000372792, PMID:10573014). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV001542539	SCV004806123	pathogenic	Stickler syndrome type 2	2024-03-25	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001542539	SCV004814132	pathogenic	Stickler syndrome type 2	2020-04-28	criteria provided, single submitter	clinical testing	The COL11A1 c.1630-2delA variant results in a substitution at the consensus splice acceptor site, which has been shown to cause skipping of exon 15 (Martin et al. 1999; Richards et al. 2010). The c.1630-2delA variant has been identified in a heterozygous state in at least six unrelated families with Stickler syndrome (Annunen et al. 1999; Martin et al. 1999; Richards et al. 2010; Acke et al. 2014). In one family, the c.1630-2delA variant was shown to segregate with disease among five affected individuals spanning three generations (Martin et al. 1999). This variant is not observed in version 2.1.1 of the Genome Aggregation Database. The variant was identified in a de novo state in the proband. Based on the collective evidence, the c.1630-2delA variant is classified as pathogenic for Stickler syndrome.
OMIM	RCV001542539	SCV000038956	pathogenic	Stickler syndrome type 2	1999-10-01	no assertion criteria provided	literature only
Genomics England Pilot Project, Genomics England	RCV001542539	SCV001759975	likely pathogenic	Stickler syndrome type 2		no assertion criteria provided	clinical testing