ClinVar

Description

Variant summary: SHOX c.(?_-692)_(-433+1_-432-1)del is located in the untranscribed region upstream of the SHOX gene region and involves exon 1. A presumed nomenclature of c.(?_-692)_(-433+1_-432-1)del has been designated for the purposes of this classification. The SHOX gene is located in a pseudoautosomal region of the X and Y chromosomes, and a similar variant allele encompassing the deletion of exon 1 was found at a frequency of 0.00065 in 21646 control chromosomes, predominantly at a frequency of 0.0054 within the East Asian subpopulation in the gnomAD Structural Variants database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 11-fold of the estimated maximal expected allele frequency for a pathogenic variant in SHOX causing Short Stature phenotype (0.0005), suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. However, deletion of exon 1 has been reported in individuals affected with Short Stature and was indicated to segregate with disease in at least one family (Shima_2016, Funari_2019). Since the expressivity of SHOX deficiency is highly variable (see e.g. PMID: 21325865), these data indicate that the variant may be associated with Short Stature, but it is unclear if it could contribute to more severe phenotypes. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic for Short Stature phenotype.