ClinVar Miner

Submissions for variant NM_000088.3(COL1A1):c.3233T>C (p.Val1078Ala) (rs767525556)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Fulgent Genetics,Fulgent Genetics RCV000765369 SCV000896634 uncertain significance Osteogenesis imperfecta with normal sclerae, dominant form; Postmenopausal osteoporosis; Osteogenesis imperfecta, recessive perinatal lethal; Osteogenesis imperfecta type III; Infantile cortical hyperostosis; Ehlers-Danlos syndrome, procollagen proteinase deficient; Osteogenesis imperfecta type I 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000521091 SCV000621444 uncertain significance not provided 2018-04-25 criteria provided, single submitter clinical testing The V1078A variant of uncertain significance in the COL1A1 gene has not been published as pathogenic or benign to our knowledge. This variant has been identified in conjunction with additional cardiogenetic variants in individuals with features of HDCT or referred for HDCT genetic testing at GeneDx. However, thus far, segregation data is limited for these individuals due to the lack of clinical information provided and insufficient participation by informative family members. In addition, V1078A is observed in 24/89,634 alleles (0.03%) from individuals of European (non-Finnish) background in large population cohorts (Lek et al., 2016). The V1078A variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Furthermore, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Finally, V1078A does not affect a glycine residue in a Gly-X-Y motif in the triple helical region of the COL1A1, where the majority of pathogenic missense variants occur (Stenson et al., 2014).
Illumina Clinical Services Laboratory,Illumina RCV000259210 SCV000404122 uncertain significance Osteogenesis Imperfecta, Dominant 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000319126 SCV000404123 uncertain significance Ehlers-Danlos syndrome, type 7A 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000355446 SCV000404124 uncertain significance Infantile cortical hyperostosis 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000695671 SCV000824185 uncertain significance Osteogenesis imperfecta type I 2018-03-27 criteria provided, single submitter clinical testing This sequence change replaces valine with alanine at codon 1078 of the COL1A1 protein (p.Val1078Ala). The valine residue is weakly conserved and there is a small physicochemical difference between valine and alanine. This variant is present in population databases (rs767525556, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with COL1A1-related disease. ClinVar contains an entry for this variant (Variation ID: 324102). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The alanine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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