ClinVar Miner

Submissions for variant NM_000088.3(COL1A1):c.1691G>A (p.Arg564His) (rs1800211)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000484361 SCV000564896 uncertain significance not specified 2017-03-27 criteria provided, single submitter clinical testing The R564H variant in the COL1A1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R564H variant is observed in 22/66634 (0.03%) alleles from individuals of non-Finnish European background in the ExAC dataset (Lek et al., 2016). The R564H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar 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. We interpret R564H as a variant of uncertain significance.
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000659352 SCV000781163 likely pathogenic Osteogenesis imperfecta type I 2016-11-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001125672 SCV001284770 uncertain significance Infantile cortical hyperostosis 2018-01-12 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 RCV001125673 SCV001284771 benign Ehlers-Danlos syndrome, procollagen proteinase deficient 2018-01-12 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Clinical Services Laboratory,Illumina RCV001125674 SCV001284772 likely benign Osteogenesis imperfecta 2018-01-12 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Invitae RCV000659352 SCV001420973 uncertain significance Osteogenesis imperfecta type I 2019-10-23 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 564 of the COL1A1 protein (p.Arg564His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs1800211, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in an individual affected with an abnormality of connective tissue (PMID: 26633542). ClinVar contains an entry for this variant (Variation ID: 418140). 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: "Not Available"; Align-GVGD: "Class C25"). 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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