Submissions for variant NM_000088.4(COL1A1):c.1243C>T (p.Arg415Ter)

dbSNP: rs72648326

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000516899	SCV000612892	pathogenic	not provided	2017-06-21	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000490754	SCV000627165	pathogenic	Osteogenesis imperfecta type I	2024-12-09	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg415*) in the COL1A1 gene. It is expected to result in an absent or disrupted protein product. 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). This premature translational stop signal has been observed in individuals with osteogenesis imperfecta, type 1 (PMID: 8613526, 8808594, 15024745, 25944380, 27132807). ClinVar contains an entry for this variant (Variation ID: 425597). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002475959	SCV000894141	pathogenic	Osteogenesis imperfecta with normal sclerae, dominant form; Osteogenesis imperfecta, perinatal lethal; Osteogenesis imperfecta type III; Infantile cortical hyperostosis; Ehlers-Danlos syndrome, arthrochalasia type; Osteogenesis imperfecta type I; Osteoporosis; Combined osteogenesis imperfecta and Ehlers-Danlos syndrome 1	2021-08-24	criteria provided, single submitter	clinical testing
GeneDx	RCV000516899	SCV001168430	pathogenic	not provided	2024-07-08	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 36709916, 37270749, 31447884, 27132807, 15741671, 8613526, 22679784, 8808594, 27748872, 31414283, 31363794, 15024745, 25944380, 31794058, 32166892, 33939306, 35909573, 35822426, 35186396, 37334733, 27535533)
Institute of Human Genetics, University of Leipzig Medical Center	RCV001262344	SCV001440169	pathogenic	Infantile cortical hyperostosis	2019-01-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000516899	SCV003826955	pathogenic	not provided	2022-12-02	criteria provided, single submitter	clinical testing
3billion, Medical Genetics	RCV003313958	SCV004013734	pathogenic	Combined osteogenesis imperfecta and Ehlers-Danlos syndrome 1		criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. The variant is predicted to 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. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000425597 / PMID: 8808594). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Neuberg Centre For Genomic Medicine, NCGM	RCV004760530	SCV005373548	pathogenic	Osteogenesis imperfecta, perinatal lethal	2023-06-02	criteria provided, single submitter	clinical testing	The observed stop gained variant c.1243C>T(p.Arg415Ter) in the COL1A1 gene has been reported previously in individuals affected with osteogenesis imperfecta (Zhang H, et al., 2016). This variant is absent in the gnomAD exomes. It is submitted to ClinVar as Pathogenic. Computational evidence (MutationTaster - Disease causing) predicts damaging effect on protein structure and function for this variant. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV004796193	SCV005416290	pathogenic	Osteogenesis imperfecta with normal sclerae, dominant form; Osteogenesis imperfecta, perinatal lethal; Osteogenesis imperfecta type III; Ehlers-Danlos syndrome, arthrochalasia type; Osteogenesis imperfecta type I; Combined osteogenesis imperfecta and Ehlers-Danlos syndrome 1		criteria provided, single submitter	clinical testing	PVS1+PM2_Supporting+PS4_Moderate+PM6_Supporting+PP4
Department of Medical Sciences, Uppsala University	RCV000490754	SCV000574589	pathogenic	Osteogenesis imperfecta type I		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004722824	SCV005340721	pathogenic	COL1A1-related disorder	2024-07-23	no assertion criteria provided	clinical testing	The COL1A1 c.1243C>T variant is predicted to result in premature protein termination (p.Arg415*). This variant was reported in multiple individuals with osteogenesis imperfecta (see example: Higuchi et al. 2021. PubMed ID: 33939306; Hruskova et al. 2016. PubMed ID: 27132807; Morlino et al. 2020. PubMed ID: 31794058). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in COL1A1 are expected to be pathogenic. This variant is interpreted as pathogenic.