ClinVar Miner

Submissions for variant NM_000088.3(COL1A1):c.2116G>A (p.Asp706Asn) (rs372215246)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000725614 SCV000338179 uncertain significance not provided 2015-12-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000320414 SCV000404149 uncertain significance Infantile cortical hyperostosis 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Clinical Services Laboratory,Illumina RCV000379767 SCV000404150 uncertain significance Osteogenesis imperfecta 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Clinical Services Laboratory,Illumina RCV000285364 SCV000404151 uncertain significance Ehlers-Danlos syndrome, procollagen proteinase deficient 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx RCV000725614 SCV000564897 uncertain significance not provided 2018-10-29 criteria provided, single submitter clinical testing The D706N variant in the COL1A1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The D706N variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The D706N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (G701C, G701S, G704C, G704S) have been reported in the Human Gene Mutation Database in association with osteogenesis imperfecta types III and IV (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret D706N as a variant of uncertain significance.
Invitae RCV000694080 SCV000822507 uncertain significance Osteogenesis imperfecta type I 2019-11-05 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 706 of the COL1A1 protein (p.Asp706Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs372215246, ExAC 0.007%). This variant has not been reported in the literature in individuals with COL1A1-related disease. ClinVar contains an entry for this variant (Variation ID: 285239). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000725614 SCV001151367 uncertain significance not provided 2020-03-01 criteria provided, single submitter clinical testing

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