ClinVar

Description

Variant summary: The variant identified by MLPA or other technology involves the deletion of exons 5-6, which includes the last exon in the TMEM38B gene. The exact breakpoint at the 3' end of this variant is unknown, and therefore this deletion might extend downstream of the assayed region of the gene. A presumed nomenclature of c.(542+1_543-1)_(*2532_?)del has been designated for the purposes of this classification. Although exact breakpoints of this deletion are not known, it is not expected to cause nonsense mediated decay (NMD), but is predicted to cause a large truncation of the encoded protein (removing amino acids ~181-291, and likely replacing it with an incorrect sequence). The variant was absent in 21346 control chromosomes (gnomAD database, structural variants dataset). To our knowledge, no occurrence of c.(542+1_543-1)_(*2532_?)del in individuals affected with Osteogenesis Imperfecta and no experimental evidence demonstrating its impact on protein function have been reported. However, a large deletion variant overlapping with our variant of interest (i.e. exon 5 deletion) was reported in affected individual(s) (HGMD), which might indicate a functional importance for the deleted protein region. No submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.