Submissions for variant NM_000089.4(COL1A2):c.2933G>A (p.Arg978His)

gnomAD frequency: 0.00002  dbSNP: rs559605075

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV002241454	SCV001404012	uncertain significance	Osteogenesis imperfecta type I; Ehlers-Danlos syndrome, classic type, 1	2023-11-28	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 978 of the COL1A2 protein (p.Arg978His). This variant is present in population databases (rs559605075, gnomAD 0.02%). This missense change has been observed in individual(s) with osteogenesis imperfecta (PMID: 29807018). ClinVar contains an entry for this variant (Variation ID: 958335). 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 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV001507702	SCV001713404	uncertain significance	not provided	2019-10-14	criteria provided, single submitter	clinical testing
GeneDx	RCV001507702	SCV004021736	uncertain significance	not provided	2023-07-06	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Occurs in the triple helical domain at the Y position in the canonical Gly-X-Y repeat; although this variant may have an effect on normal protein folding and function, missense substitution at the Y position is not a common mechanism of disease (HGMD); This variant is associated with the following publications: (PMID: 29807018, 37076969)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323826	SCV004029033	uncertain significance	not specified	2023-07-17	criteria provided, single submitter	clinical testing	Variant summary: COL1A2 c.2933G>A (p.Arg978His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5e-05 in 242154 control chromosomes. The observed variant frequency is approximately 9.91 fold of the estimated maximal expected allele frequency for a pathogenic variant in COL1A2 causing Osteogenesis Imperfecta phenotype (5e-06), suggesting that the variant may be benign. c.2933G>A has been reported in the literature in individuals with Osteogenesis Imperfecta Type IV, one patient carried a second allele more likely to explain the patients phenotype while the second carried only the variant of interest (e.g., Mohd Nawawi_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 29807018). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.