ClinVar Miner

Submissions for variant NM_000088.3(COL1A1):c.1042G>A (p.Ala348Thr) (rs139955975)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Centre for Genomic and Experimental Medicine,University of Edinburgh RCV000599940 SCV000731244 likely pathogenic Thoracic aortic aneurysm and aortic dissection no assertion criteria provided research
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000521409 SCV000857101 uncertain significance not provided 2017-10-02 criteria provided, single submitter clinical testing
GeneDx RCV000521409 SCV000618069 uncertain significance not provided 2018-04-23 criteria provided, single submitter clinical testing The A348T variant in the COL1A1 gene has not been published as pathogenic or been reported as benign to our knowledge. The A348T variant has been observed in 32/104,648 (0.03%) alleles from individuals of non-Finnish European ancestry in large population cohorts (Lek et al., 2016). The A348T variant 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. However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. We interpret A348T as a variant of uncertain significance.
Illumina Clinical Services Laboratory,Illumina RCV000262664 SCV000404185 uncertain significance Infantile cortical hyperostosis 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000320157 SCV000404186 uncertain significance Ehlers-Danlos syndrome, type 7A 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000367913 SCV000404187 uncertain significance Osteogenesis Imperfecta, Dominant 2016-06-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000029552 SCV000052204 uncertain significance not specified 2018-02-28 criteria provided, single submitter clinical testing Variant summary: COL1A1 c.1042G>A (p.Ala348Thr) results in a non-conservative amino acid change located in the Collagen triple helix repeat of the encoded protein sequence. Although A348T does not affect a Glycine residue in a Gly-X-Y motif in the triple helical region of the COL1A1 gene, where the majority of pathogenic missense variants occur. At-least three of five in-silico tools evaluated predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00027 in 36540 control chromosomes. The observed variant frequency is approximately 9.73 fold of the estimated maximal expected allele frequency for a pathogenic variant in COL1A1 causing Osteogenesis Imperfecta phenotype (2.8e-05). However, only 10 occurrences were found in controls, which is too low to make a conclusion. To our knowledge, no occurrence of c.1042G>A in individuals affected with Osteogenesis Imperfecta and no experimental evidence demonstrating its impact on protein function have been reported. At-least one internal co-occurrence with other pathogenic variant(s) have been reported (COL1A2 c.639+2T>G), providing supporting evidence for a benign role. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000560142 SCV000627159 uncertain significance Osteogenesis imperfecta type I 2018-12-18 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 348 of the COL1A1 protein (p.Ala348Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs139955975, ExAC 0.05%), 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: 35897). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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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