ClinVar Miner

Submissions for variant NM_000089.4(COL1A2):c.2133+6T>A

dbSNP: rs72658164
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002231011 SCV000627308 pathogenic Osteogenesis imperfecta type I; Ehlers-Danlos syndrome, classic type, 1 2022-11-28 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant disrupts the triple helix domain of COL1A2. Glycine residues within the Gly-Xaa-Yaa repeats of the triple helix domain are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236). In COL1A2, variants affecting these glycine residues are significantly enriched in individuals with disease (PMID: 9016532, 17078022) compared to the general population (ExAC). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 35, but is expected to preserve the integrity of the reading-frame (PMID: 16705691). ClinVar contains an entry for this variant (Variation ID: 456815). This variant has been observed in individual(s) with autosomal dominant osteogenesis imperfecta (PMID: 16705691, 30715774). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 35 of the COL1A2 gene. It does not directly change the encoded amino acid sequence of the COL1A2 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product.
Medical Genetics Laboratory, West China Hospital, Sichuan University RCV001255997 SCV001371682 pathogenic Osteogenesis imperfecta, perinatal lethal criteria provided, single submitter in vitro The clinical manifestation of the proband and his family members- the lower limbs are bent out of shape and/or has enamel defect. In vitro Minigene studies indicate that the variants interrupted its normal splicing process .

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