Submissions for variant NM_001854.4(COL11A1):c.3816+1G>A

dbSNP: rs398122828

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000579344	SCV000335759	pathogenic	not provided	2015-09-29	criteria provided, single submitter	clinical testing
GeneDx	RCV000579344	SCV000680761	pathogenic	not provided	2022-04-13	criteria provided, single submitter	clinical testing	Canonical splice site variant expected to result in aberrant splicing; sequencing of cDNA prepared from patient fibroblasts demonstrated in-frame deletion of 18 amino acid codons in the triple helical domain, consistent with exon skip (Griffith et al., 1998); Deletions involving coding exons in this gene are frequently reported as pathogenic, regardless of frame prediction (HGMD); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17236192, 34589056, 19449424, 25240749, 25525159, 9529347, 28983407, 25073711, 30020262, 33502061, 34006472, 33951325)
Ambry Genetics	RCV000623510	SCV000741536	pathogenic	Inborn genetic diseases	2024-02-23	criteria provided, single submitter	clinical testing	The c.3816+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 50 of the COL11A1 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay. The exact functional effect of the altered amino acid sequence is unknown. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been reported to segregate in affected individuals from multiple families with features consistent with Type XI collagenopathy (Ala-Kokko, 2009; Bacciu, 2018; Griffith, 1998; Khalifa, 2014). Additional unrelated affected individuals have been reported (Acke, 2014; Khan, 2021; Scocchia, 2021; Yu, 2021). This nucleotide position is highly conserved in available vertebrate species. RNA studies have demonstrated that this alteration results in abnormal splicing (Griffith, 1998). In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. Based on the available evidence, this alteration is classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000579344	SCV002233649	pathogenic	not provided	2023-10-23	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 50 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 Marshall or Stickler syndrome (PMID: 9529347, 19449424, 25240749). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is also known as IVS50+1G>A. ClinVar contains an entry for this variant (Variation ID: 39776). Studies have shown that disruption of this splice site results in skipping of exon 51, but is expected to preserve the integrity of the reading-frame (PMID: 9529347). For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV002468558	SCV002764981	pathogenic	Stickler syndrome type 2	2021-04-22	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000579344	SCV002817261	pathogenic	not provided	2021-08-17	criteria provided, single submitter	clinical testing	The majority of patients reported with this variant are described as having Marshall syndrome (PMID 17236192, 9529347, 19449424, 3002026, 25073711) although some are also described as having Stickler syndrome (PMID 97928857, 25240749). This variant segregates with disease in multiple families (PMID 9529347, 30020262, 25073711). Computational tools yielded predictions that this variant may interfere with normal RNA splicing. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org).This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV003313929	SCV004013169	pathogenic	COL11A1-related disorder	2023-05-03	criteria provided, single submitter	clinical testing	PS3, PS4, PM2, PM6, PP1, PP3_Strong
OMIM	RCV000032995	SCV000038953	pathogenic	Marshall syndrome	2007-02-01	no assertion criteria provided	literature only
Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital	RCV000032995	SCV001482318	pathogenic	Marshall syndrome	2019-05-31	no assertion criteria provided	research