ClinVar Miner

Submissions for variant NM_000089.3(COL1A2):c.3047C>A (p.Pro1016His) (rs377278762)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000723559 SCV000331314 uncertain significance not provided 2015-06-10 criteria provided, single submitter clinical testing
GeneDx RCV000723559 SCV000590226 uncertain significance not provided 2018-03-06 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the COL1A2 gene. The P1016H variant has been previously reported in one Swedish individual in association with osteogenesis imperfecta type IV (Lindahl et al., 2015); however, no further clinical details or segregation studies were reported. This variant is also observed in 1/4566 (0.02%) alleles from individuals of Latino ancestry, and in 5/34800 (0.01%) alleles from individuals of Non-Finnish European ancestry, in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a position that is not conserved across species and histidine (H) is the wild-type residue at this position in multiple mammalian species. Although P1016H is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties, in silico analysis predicts this variant likely does not alter the protein structure/function. Finally, P1016H is also classified in ClinVar as a variant of uncertain significance by another clinical laboratory (ClinVar SCV000331314.2; Landrum et al., 2016).
Invitae RCV000526237 SCV000627331 uncertain significance Ehlers-Danlos syndrome, classic type; Osteogenesis imperfecta type I 2019-08-14 criteria provided, single submitter clinical testing This sequence change replaces proline with histidine at codon 1016 of the COL1A2 protein (p.Pro1016His). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and histidine. This variant is present in population databases (rs377278762, ExAC 0.02%). This variant has been reported in an individual affected with osteogenesis imperfecta (OI) (PMID: 25944380). This individual has also been reported in an entry in the Leiden Open-source Variation Database (LOVD), which states that the same variant was detected in the proband's unaffected father and affected sibling (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 281098). 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 histidine 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. In summary, this variant is a rare missense change that is not predicted to affect protein function. It has been reported in both the population and affected individuals, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics,Fulgent Genetics RCV000764736 SCV000895871 uncertain significance Osteogenesis imperfecta with normal sclerae, dominant form; Postmenopausal osteoporosis; Osteogenesis imperfecta, recessive perinatal lethal; Osteogenesis imperfecta type III; Ehlers-Danlos syndrome, autosomal recessive, cardiac valvular form; EHLERS-DANLOS SYNDROME, ARTHROCHALASIA TYPE, 2 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001162767 SCV001324732 likely benign EHLERS-DANLOS SYNDROME, ARTHROCHALASIA TYPE, 2 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 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.
Illumina Clinical Services Laboratory,Illumina RCV001162768 SCV001324733 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.

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