Submissions for variant NM_000088.4(COL1A1):c.934C>T (p.Arg312Cys)

dbSNP: rs72645347

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000415259	SCV000492940	likely pathogenic	Bruising susceptibility; Fragile skin; Joint hypermobility	2014-12-03	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000631472	SCV000752552	pathogenic	Osteogenesis imperfecta type I	2023-04-28	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 312 of the COL1A1 protein (p.Arg312Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with EDS and Ehlers-Danlos syndrome (EDS) (PMID: 10739762, 17211858, 23587214, 25597651, 28102596). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17343). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt COL1A1 protein function. For these reasons, this variant has been classified as Pathogenic.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001198512	SCV001369472	likely pathogenic	Osteogenesis imperfecta with normal sclerae, dominant form	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Likely pathogenic.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002276563	SCV002565547	pathogenic	Ehlers-Danlos syndrome	2019-10-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002496407	SCV002810468	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	2022-03-29	criteria provided, single submitter	clinical testing
GeneDx	RCV003225023	SCV003921700	pathogenic	not provided	2022-10-31	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Located in the Gly-Xaa-Yaa triple helical region of the pro-alpha1(I) chain encoded by the COL1A1 gene, where triplet glycine substitutions are the most common cause of osteogenesis imperfecta (OI). The effect of missense substitution at the X and Y positions are more difficult to predict; however, multiple variants that result in introduction of a Cys residue in pro-alpha1(I) have been reported to be pathogenic (Dalgleish, 1998); This variant is associated with the following publications: (PMID: 25597651, 10739762, 28102596, 30261568, 32736638, 9399846, 35587586, 35128800, 32369273, 31323331, 34265140, 34712265, 35205310, 35822426, 34484741, 35154279, 31531849)
CeGaT Center for Human Genetics Tuebingen	RCV003225023	SCV004009814	pathogenic	not provided	2023-06-01	criteria provided, single submitter	clinical testing	COL1A1: PP1:Strong, PM2, PM6, PS4:Moderate, PP2, PS3:Supporting
OMIM	RCV000018884	SCV000039168	pathogenic	Ehlers-Danlos syndrome, classic type	2000-04-01	no assertion criteria provided	literature only
GeneReviews	RCV000018884	SCV002600137	not provided	Ehlers-Danlos syndrome, classic type		no assertion provided	literature only