ClinVar Miner

Submissions for variant NM_000088.3(COL1A1):c.2932C>T (p.Pro978Ser) (rs193922153)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Human Genetics, Inc RCV000680480 SCV000807858 likely benign Connective tissue disorder 2018-06-01 criteria provided, single submitter clinical testing
Centre for Genomic and Experimental Medicine,University of Edinburgh RCV000607797 SCV000731242 likely pathogenic Thoracic aortic aneurysm and aortic dissection no assertion criteria provided research
GeneDx RCV000608881 SCV000715752 likely benign not specified 2017-10-13 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Integrated Genetics/Laboratory Corporation of America RCV000608881 SCV000052225 likely benign not specified 2019-02-09 criteria provided, single submitter clinical testing Variant summary: The variant, COL1A1 c.2932C>T (p.Pro978Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 276226 control chromosomes (gnomAD). The observed variant frequency is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant in COL1A1 causing Osteogenesis Imperfecta phenotype (2.8e-05), strongly suggesting that the variant is benign. The variant, c.2932C>T has been reported in the literature in individuals affected with Osteogenesis Imperfecta and Thoracic Aortic Aneurysm/Aortic Dissection (Pollitt_2006, Weerakkody_2018). These reports however do not provide unequivocal conclusions about association of the variant with Osteogenesis Imperfecta. Co-occurrence with another pathogenic variant (in cis) has been reported (COL1A1, c.2644 C>T (p.R882X)), for this variant, further providing a supporting evidence for its benign role. This other variant (p.R882X) segregated with disease in this family. Furthermore, as it lies upstream of this variant (p.P978S), the authors concluded that it is unlikely to affect the resultant phenotype in this family. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (2X likely benign and 1X Uncertain significance). Based on the evidence outlined above, the variant was classified as likely benign.
Invitae RCV000537025 SCV000627217 uncertain significance Osteogenesis imperfecta type I 2018-12-06 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 978 of the COL1A1 protein (p.Pro978Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs193922153, ExAC 0.07%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in an individual with osteogenesis imperfecta, however this individual also carried a pathogenic variant in COL1A1 on the same chromosome (in cis) (PMID: 16786509). ClinVar contains an entry for this variant (Variation ID: 35918). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but 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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