ClinVar

This variant is classified as a variant of unknown significance because its contribution to an intellectual developmental disorder with poor growth and scoliosis has not been confirmed.

In 4 affected members of a highly consanguineous Saudi family with an intellectual developmental disorder with poor growth and scoliosis, Umair et al. (2021) identified a homozygous c.947A-G transition (c.947A-G, NM_015058.1) in exon 8 of the VWA8 gene, resulting in an asp316-to-gly (D316G) substitution at a highly conserved residue. The variant, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was present 5 times in heterozygous state (5 of 125,748 exomes) but was not present in homozygous state in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but molecular modeling predicted that the variant would destabilize VWA8 protein structure. The variant was classified as a variant of unknown significance according to ACMG criteria. The patients, who ranged from 8 to 19 years of age, had global developmental delay with mild to moderately impaired intellectual development, poor or absent speech, and poor overall growth. The female proband could not walk and was wheelchair-bound with central hypotonia, spastic diplegia, contractures of the lower limbs, severe scoliosis, and fused ribs (spondylocostal dysostosis). She also had a large atrial septal defect. Her 3 brothers were similarly affected (although without heart defects); 1 had clubfoot. All patients had astigmatism, and 2 had exotropia and amblyopia. Brain imaging was normal in all patients.