Submissions for variant NM_000088.4(COL1A1):c.1299+5G>A

dbSNP: rs193922139

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000029555	SCV000052207	likely pathogenic	Osteogenesis imperfecta	2019-01-22	criteria provided, single submitter	clinical testing	Variant summary: COL1A1 c.1299+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5' splicing donor site. Two predict the variant weakens a 5' donor site (ACMG PP3). However, these predictions have yet to be confirmed by functional studies. The variant was absent in 241188 control chromosomes (ACMG PM2). c.1299+5G>A has been reported in the literature in at-least two individuals affected with Osteogenesis Imperfecta type I (Schleit_2015) (ACMG PS4). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000688895	SCV000816522	pathogenic	Osteogenesis imperfecta type I	2022-10-18	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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: 35900). This variant is also known as IVS19+5G>A. This variant has been observed in individuals with osteogenesis imperfecta (PMID: 25963598; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 19 of the COL1A1 gene. It does not directly change the encoded amino acid sequence of the COL1A1 protein. It affects a nucleotide within the consensus splice site.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000688895	SCV001428831	pathogenic	Osteogenesis imperfecta type I	2018-12-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002381264	SCV002689788	likely pathogenic	Cardiovascular phenotype	2022-03-25	criteria provided, single submitter	clinical testing	The c.1299+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 19 in the COL1A1 gene. This variant has been reported in the literature in individuals reported to have osteogenesis imperfecta (OI) and has been observed in at least one additional individual with a personal and/or family history consistent with OI (Schleit J et al. Hum Mutat, 2015 Jul;36:728-39; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. 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 majority of available evidence to date, this variant is likely to be pathogenic.