Submissions for variant NM_000089.4(COL1A2):c.982G>A (p.Gly328Ser)

dbSNP: rs66612022

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV002231248	SCV000627364	pathogenic	Osteogenesis imperfecta type I; Ehlers-Danlos syndrome, classic type, 1	2023-11-04	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 328 of the COL1A2 protein (p.Gly328Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant osteogenesis imperfecta (PMID: 7860070, 9272740, 16705691, 17078022, 22589248). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 456848). 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 COL1A2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects COL1A2 function (PMID: 7860070, 9272740, 9594376). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000763174	SCV000893765	pathogenic	Osteogenesis imperfecta with normal sclerae, dominant form; Postmenopausal osteoporosis; Osteogenesis imperfecta, perinatal lethal; Osteogenesis imperfecta type III; Ehlers-Danlos syndrome, cardiac valvular type; Ehlers-danlos syndrome, arthrochalasia type, 2	2018-10-31	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001196500	SCV001367108	pathogenic	Osteogenesis imperfecta with normal sclerae, dominant form	2019-09-09	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM1,PM2,PM5,PP3.
GeneDx	RCV001783030	SCV002064157	pathogenic	not provided	2022-01-18	criteria provided, single submitter	clinical testing	Observed frequently in unrelated patients with osteogenesis imperfecta from different ethnic backgrounds in published literature (Lee et al., 2006; Marini et al., 2007; Bardai et al., 2016; Ho Duy et al., 2016) and not observed in controls; Occurs in the triple helical domain and replaces the glycine in the 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 (HGMD); Not observed 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: 22589248, 15024745, 27509835, 9594376, 31414283, 9272740, 32123938, 31853946, 32659730, 16705691, 26307460, 21667357, 24668929, 17875077, 27519266, 29907962, 7860070, 31447884, 17078022, 29453417, 32770541)
DASA	RCV001836645	SCV002097304	pathogenic	Ehlers-Danlos syndrome, cardiac valvular type	2022-02-14	criteria provided, single submitter	clinical testing	Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 32659730) - PS3_supporting. The c.982G>A;p.(Gly328Ser) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 456848; PMID: 22589248; 16705691; 9272740; 27519266; 26307460) - PS4. This variant is not present in population databases (rs66612022, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Pathogenic missense variant in this residue have been reported (Clinvar ID: 618025; 372735) - PM5. The variant co-segregated with disease in multiple affected family members (PMID: 26307460) - PP1. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic.
Lake Erie College Of Osteopathic Medicine, Lecom Bradenton	RCV003448980	SCV003932630	pathogenic	Osteogenesis imperfecta	2023-06-16	no assertion criteria provided	clinical testing	Osteogenesis Imperfecta, indeterminate type