ClinVar Genomic variation as it relates to human health

Identified in patients from large cohorts undergoing whole exome or whole genome sequencing in the literature, but additional clinical information and familial segregation data were not provided (Posey et al., 2017; Hou et al., 2020); Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 31980526, 27959697)

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as pathogenic [PMID 27959697]

Variant summary: COL9A1 c.876+2T>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: four predict the variant abolishes a 5 prime splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 6.8e-05 in 250662 control chromosomes. c.876+2T>A has been reported in the literature in one individual affected with COL9A1-Related Disorder. This report does not provide unequivocal conclusions about association of the variant with COL9A1-Related Disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (pathogenic/likely pathogenic n=5, VUS n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.

This sequence change affects a donor splice site in intron 8 of the COL9A1 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 COL9A1 are known to be pathogenic (PMID: 16909383, 21421862). This variant is present in population databases (rs149830493, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with COL9A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 374336). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Our laboratory has reported dual molecular diagnoses in COL9A1 (NM_001851.4:c.876+2T>A) and ATRX (NM_000489.3:c.569C>T) in an individual with prematurity with intrauterine growth retardation, profound failure to thrive and global developmental delay, congenital heart disease, visual impairment, severe scoliosis, hypertonia/spasticity, joint contractures, microcephaly, intellectual disability, structural brain abnormality, bowel malrotation and obstruction, short stature, dysmorphic features, cleft uvula, genital anomalies and organomegaly.

The COL9A1 c.876+2T>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant was reported in a 9 year-old male through whole exome sequencing and was classified as pathogenic with an autosomal dominant mode of inheritance (Table S5, Posey et al 2017. PubMed ID: 27959697) and was also reported in the heterozygous state in a patient with small for gestational age with persistent short stature (Toni et al. 2023. PubMed ID: 37019085). However, other studies have demonstrated an autosomal recessive inheritance for Stickler syndrome with a loss-of-function mutation in COL9A1 (Van Camp et al. 2006. PubMed ID: 16909383; Nikopoulos et al. 2011. PubMed ID: 21421862). This variant is reported in 0.014% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.