ClinVar Genomic variation as it relates to human health

A variant of uncertain significance has been identified in the COL1A1 gene. The A628T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The A628T 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. This substitution occurs at a position where only amino acids with similar properties to Alanine are tolerated across species. The A628T variant is located in the Gly-Xaa-Yaa triple helical region of the pro-alpha1(I) chain encoded by the COL1A1 gene. However, while triplet glycine substitutions are the most common cause of osteogenesis imperfecta (OI), the effect of missense substitution at the X and Y positions are more difficult to predict. In addition, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Furthermore, the Exome Aggregation Consortium (ExAC) and the 1000 Genomes Project reports A628T was observed in 5/11,578 alleles from individuals of Latino background and 2/694 alleles from individuals of Ad Mixed American background, respectively.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

BS1, PP2

Variant summary: COL1A1 c.1882G>A (p.Ala628Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00023 in 251420 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 8.34 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. To our knowledge, no occurrence of c.1882G>A in individuals affected with Osteogenesis Imperfecta and no experimental evidence demonstrating its impact on protein function have been reported. Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=5) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign.

The p.A628T variant (also known as c.1882G>A), located in coding exon 28 of the COL1A1 gene, results from a G to A substitution at nucleotide position 1882. The alanine at codon 628 is replaced by threonine, an amino acid with similar properties. This variant was detected in the compound heterozygous state with another variant in COL1A1, p.R528H (c.1583G>A), in an individual with mitral valve prolapse, aortic dilatation, and heterotaxy (Jin SC et al. Nat. Genet., 2017 Nov;49:1593-1601). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.