Submissions for variant NM_000088.4(COL1A1):c.1792C>T (p.Arg598Ter)

dbSNP: rs72651614

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000490706	SCV000627186	pathogenic	Osteogenesis imperfecta type I	2023-11-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg598*) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with osteogensis imperfecta (PMID: 24501682, 27044453). ClinVar contains an entry for this variant (Variation ID: 425603). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001555740	SCV001777200	pathogenic	not provided	2020-07-06	criteria provided, single submitter	clinical testing	Reported as a potential COL1A1 hotspot variant in individuals with OI (Li et al., 2019; Osteogenesis Imperfecta Variant Database); 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 a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 30614853, 27044453, 25944380, 24501682, 15106082, 25525159)
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002279255	SCV002565134	pathogenic	Osteogenesis imperfecta	2020-02-01	criteria provided, single submitter	clinical testing
3billion	RCV002283484	SCV002573133	pathogenic	Osteogenesis imperfecta with normal sclerae, dominant form	2022-09-01	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Stop-gained (nonsense) 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 without evidence for the classification (ClinVar ID: VCV000425603 / PMID: 15106082). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Revvity Omics, Revvity	RCV001555740	SCV004235079	pathogenic	not provided	2023-06-29	criteria provided, single submitter	clinical testing
Department of Medical Sciences, Uppsala University	RCV000490706	SCV000574596	pathogenic	Osteogenesis imperfecta type I		no assertion criteria provided	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000490706	SCV004807917	uncertain significance	Osteogenesis imperfecta type I	2024-03-29	flagged submission	clinical testing
Autoinflammatory diseases unit, CHU de Montpellier	RCV000490706	SCV005381993	pathogenic	Osteogenesis imperfecta type I	2024-10-02	no assertion criteria provided	clinical testing