Submissions for variant NM_000088.4(COL1A1):c.2155G>A (p.Gly719Ser)

dbSNP: rs72651645

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Personalized Medicine, Children's Hospital Los Angeles	RCV000584774	SCV000692547	pathogenic	Dentinogenesis imperfecta; Recurrent fractures	2016-03-15	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001245339	SCV001418621	pathogenic	Osteogenesis imperfecta type I	2023-10-16	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 719 of the COL1A1 protein (p.Gly719Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with osteogenesis imperfecta (PMID: 7691343, 24668929, 25944380, 27509835, 29807018). In at least one individual the variant was observed to be de novo. This variant is also known as Gly541Ser. ClinVar contains an entry for this variant (Variation ID: 425606). 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. This variant disrupts the triple helix domain of COL1A1. Glycine residues within the Gly-Xaa-Yaa repeats of the triple helix domain are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236). In COL1A1, variants affecting these glycine residues are significantly enriched in individuals with disease (PMID: 9016532, 17078022) compared to the general population (ExAC). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001584200	SCV001812235	pathogenic	not provided	2022-06-14	criteria provided, single submitter	clinical testing	Occurs in the triple helical domain and replaces a glycine in a canonical Gly-X-Y repeat; missense substitution of a canonical glycine residue is expected to disrupt normal protein folding and function, and this is an established mechanism of disease (Jovanovic et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 7691343, 27509835, 29542187, 29807018, 26615125, 25944380, 17078022, 21667357, 24668929, 32502767, 34007986)
Blueprint Genetics	RCV001584200	SCV001832448	pathogenic	not provided	2019-11-30	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV001245339	SCV002073043	pathogenic	Osteogenesis imperfecta type I		criteria provided, single submitter	clinical testing	The missense variant p.G719S in COL1A1 (NM_000088.4) has been previously reported in multiple affected patients (Lindahl K et al; Mohd Nawawi N et al). The variant has been submitted to ClinVar as Pathogenic. It has also been reported as Gly541Ser. It affects a glycine residue in the collagen triple helix. Glycine substitutions are majorly disease causing.The p.G719S variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.G719S missense variant is predicted to be damaging by both SIFT and PolyPhen2. The glycine residue at codon 719 of COL1A1 is conserved in all mammalian species. The nucleotide c.2155 in COL1A1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Department of Medical Sciences, Uppsala University	RCV000490715	SCV000574602	pathogenic	Osteogenesis imperfecta type III		no assertion criteria provided	clinical testing