ClinVar Genomic variation as it relates to human health

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0104 - Dominant Negative is a mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0209 - Splice variant (canonical or non-canonical) proven to affect splicing/expression of the transcript with uncertain effect on protein structure (PMID: 25963598). (P) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (P) 0704 - Comparable variant has low previous evidence for pathogenicity. A different variant in the same splice site (c.1299+1G>C) has also been shown to cause Osteogenesis imperfecta (ClinVar, PMID: 15024692). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. The variant has been previously reported as pathogenic in patients with Osteogenesis imperfecta (ClinVar, PMID: 12590186, 22753364, 19358256, 25963598). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign

Published functional studies demonstrate variant results in skipping of exon 19 (Schleit et al., 2015); Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30886339, 32234057, 25525159, 12590186, 27510842, 22206639, 19358256, 25963598, 30715774, 33939306)

This variant is expected to severely impact normal RNA splicing, and consequently, protein structure and/or function. This variant has been identified in at least one individual with clinical features associated with osteogenesis imperfecta. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org).

This sequence change affects a donor splice site in intron 19 of the COL1A1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in COL1A1 are known to be pathogenic (PMID: 7942841, 9295084, 9443882). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with type 1 osteogenesis imperfecta (PMID: 12590186, 19358256, 22753364, 25963598, 27510842). ClinVar contains an entry for this variant (Variation ID: 425599). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

The COL1A1 c.1299+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported in individuals with mild osteogenesis imperfecta (OI) (see example: reported as IVS19+1G>A, Benusiene et al. 2003. PubMed ID: 12590186; Higuchi et al. 2021. PubMed ID: 33939306). Furthermore, an alternate nucleotide at the same position, c.1299+1G>C, has been reported in an individual with OI type IV (Figure 1B, Cabral and Marini et al. 2004. PubMed ID: 15024692). The c.1299+1G>A variant has not been reported in a large population database, indicating this variant is rare. Variants that disrupt the consensus splice donor site in COL1A1 are expected to be pathogenic. This variant is interpreted as pathogenic.