ClinVar Genomic variation as it relates to human health

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.

Variant summary: COL1A1 c.3766G>A (p.Ala1256Thr) results in a non-conservative amino acid change located in the Fibrillar collagen, C-terminal domain (IPR000885) of the encoded protein sequence. Five 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 250554 control chromosomes (gnomAD), predominantly at a frequency of 0.0021 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 75 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 a benign polymorphism found primarily in populations of East Asian origin. c.3766G>A has been reported in the literature in individuals affected with Osteogenesis Imperfecta, although with no evidence for familial transmission (Zhang_2012, Ho Duy_2016). In one affected compound heterozygous individual, the variant of interest was inherited from an unaffected mother and a pathogenic splice variant (COL1A1 c.1354-12G>A) was inherited from an affected father who had additional family history of Osteogenesis Imperfecta (Li_2019), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters have assessed the variant since 2014: two classified the variant as uncertain significance, two as likely benign, and one as benign. Based on the evidence outlined above, the variant was classified as benign.

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

This variant is associated with the following publications: (PMID: 27519266, 25146735, 26901136, 21667357)

The COL1A1 c.3766G>A variant is predicted to result in the amino acid substitution p.Ala1256Thr. This variant has been reported as heterozygous in at least three patients with osteogenesis imperfecta although hearing loss status was not clearly indicated (Zhang et al. 2012. PubMed ID: 21667357; Ho Duy et al. 2016. PubMed ID: 27519266; Zhytnik et al. 2020. PubMed ID: 32166892). This variant has been reported in 0.19% of East Asian descent in gnomAD. This variant could be benign. However, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

COL1A1 encodes type I collagens, which are the major components of the corneal stroma and basement membranes. The amounts of collagen type I and type V are important for maintaining the stroma organization and shape and strength of the cornea. In this study, a heterozygous variant c.3766G>A in COL1A1 was detected in family 2, which is located in exon 18 and causes a p.A1256T amino acid change.