ClinVar Miner

Submissions for variant NM_000088.3(COL1A1):c.3196C>T (p.Arg1066Cys) (rs72654799)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000485287 SCV000568543 likely pathogenic not provided 2016-11-04 criteria provided, single submitter clinical testing The R1066C variant in the COL1A1 gene has been reported previously in four affected individuals from one family with combined features of both osteogenesis imperfecta (OI) and Ehlers-Danlos syndrome including low bone density, childhood fractures of long and small bones, and large joint hyperextensibility (Cabral et al., 2007). The R1066C variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R1066C variant is a non-conservative amino acid substitution and occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The R1066C variant is 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 OI. The effect of missense substitution at the X and Y positions are more difficult to predict. Cabral et al. (2007) performed protein studies on patient-derived cultured dermal fibroblasts, and the R1066C variant was associated with decreased type I collagen molecule stability and resistance to N-proteinase cleavage. In addition, dermal collagen fibril formation was abnormal by electron microscopy in two affected family members (Cabral et al., 2007). Missense variants in nearby residues (G1061S, G1061D, G1064A) have been reported in the Human Gene Mutation Database in association with OI (Stenson et al., 2014), supporting the functional importance of this region of the protein. The R1066C variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Invitae RCV000794277 SCV000933673 uncertain significance Osteogenesis imperfecta type I 2018-10-22 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 1066 of the COL1A1 protein (p.Arg1066Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs72654799, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed to segregate with an overlapping Ehlers-Danlos syndrome and osteogenesis imperfecta type 1 phenotype in a family (PMID: 17206620). It is also reported in another family in which the individuals affected with osteogenesis imperfecta were compound heterozygotes for this variant and a second variant in the same COL1A1 gene (c.2522delC; p.Pro841Leufs*266). The unaffected father only carried the c.3196C>T variant (PMID:28436160). ClinVar contains an entry for this variant (Variation ID: 420060). This variant is also known as R888C in the literature. Experimental studies in patient derived fibroblasts have shown that this missense change causes reduction in dimer formation efficiency, reduction in thermal stability, resistance to N terminal collagen processing, and decreased fibrillar density as compared to normal controls. (PMID: 17206620). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.

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