Submissions for variant NM_000088.4(COL1A1):c.1821+1G>A

dbSNP: rs66555264

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000599354	SCV000709943	pathogenic	not provided	2022-07-19	criteria provided, single submitter	clinical testing	Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease (Stover et al., 1993); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25944380, 8408653, 25525159, 10931857, 9295084, 7942841, 9443882, 30614853, 9067755, 28810924, 33470886, 33939306, 17078022, 15931785)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000490727	SCV000752560	pathogenic	Osteogenesis imperfecta type I	2024-11-16	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 26 of the COL1A1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in COL1A1 are known to be pathogenic (PMID: 7942841, 9295084, 9443882). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with osteogenesis imperfecta (PMID: 8408653, 9067755, 10931857, 15931785, 17078022). This variant is also known as IVS26+1G>A. ClinVar contains an entry for this variant (Variation ID: 425580). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics	RCV000599354	SCV000841063	pathogenic	not provided	2018-04-23	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763410	SCV000894139	pathogenic	Osteogenesis imperfecta with normal sclerae, dominant form; Postmenopausal osteoporosis; Osteogenesis imperfecta, perinatal lethal; Osteogenesis imperfecta type III; Infantile cortical hyperostosis; Ehlers-Danlos syndrome, arthrochalasia type; Osteogenesis imperfecta type I	2018-10-31	criteria provided, single submitter	clinical testing
Mendelics	RCV000490727	SCV001140690	pathogenic	Osteogenesis imperfecta type I	2019-05-28	criteria provided, single submitter	clinical testing
DASA	RCV002221545	SCV002498810	pathogenic	Osteogenesis imperfecta	2022-04-10	criteria provided, single submitter	clinical testing	The c.1821+1G>A variant is located in a canonical splice-site, and it is not predicted the protein reading frame alteration, however, occur in a critical region and the variant disrupts <10% of protein - PVS1_moderate. Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 8408653) - PS3_moderate. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID:425580; PMID: 33939306; PMID: 33928192; PMID: 28810924; PMID: 32166892) - PS4. This variant is not present in population databases (rs66555264- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br) - PM2. The variant co-segregated with disease in multiple affected family members (PMID: 33928192; 33228694) - PP1_strong. In summary, the currently available evidence indicates that the variant is pathogenic
PreventionGenetics, part of Exact Sciences	RCV004551601	SCV004105013	pathogenic	COL1A1-related disorder	2023-07-13	criteria provided, single submitter	clinical testing	The COL1A1 c.1821+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant was reported to be causative for osteogenesis imperfecta (Stover et al. 1993. PubMed ID: 8408653; Zhytnik et al. 2020. PubMed ID: 32166892; Higuchi et al. 2021. PubMed ID: 33939306). mRNA studies showed that this variant results in intron 26 retention leading to a frameshift and premature protein termination (Stover et al. 1993. PubMed ID: 8408653). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Variants that disrupt the consensus splice donor site in COL1A1 are expected to be pathogenic. This variant is interpreted as pathogenic.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000599354	SCV005197553	pathogenic	not provided	2023-12-06	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004992266	SCV005555243	pathogenic	Cardiovascular phenotype	2024-07-02	criteria provided, single submitter	clinical testing	The c.1821+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 26 of the COL1A1 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. 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. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown. This mutation has been reported in multiple subjects with osteogenesis imperfecta (OI) including a de novo occurrence (K&ouml;rkk&ouml; J et al. Hum Mutat, 1997;9:148-56; Stover ML et al. J Clin Invest, 1993 Oct;92:1994-2002; Higuchi Y et al. Mol Genet Genomic Med, 2021 Jun;9:e1675; Holtz AP et al. Bone, 2023 Apr;169:116683; Mei Y et al. Front Endocrinol (Lausanne), 2022 Jul;13:935905). This variant has also been reported to segregate with disease in two families with OI (Zhytnik L et al. BMC Med Genomics, 2020 Nov;13:177; Doolan E et al. BMJ Open Ophthalmol, 2021 Apr;6:e000684). 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. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.
OMIM	RCV000490727	SCV000039152	pathogenic	Osteogenesis imperfecta type I	1993-10-01	no assertion criteria provided	literature only
Department of Medical Sciences, Uppsala University	RCV000490727	SCV000574571	pathogenic	Osteogenesis imperfecta type I		no assertion criteria provided	clinical testing