ClinVar

Description

Variant summary: HS6ST1 c.1121G>A (p.Ser374Asn) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00084 in 247676 control chromosomes (i.e., 209 carriers; gnomAD v2.1 Exomes dataset). The available data on variant occurrences in the general population are insufficient to allow clear conclusions about variant significance. c.1121G>A has been reported in the literature in individuals affected with demyelinating neuropathy and a severe motor disability (e.g., Antona_2020), premature ovarian insufficiency (e.g., Jaillard_2020), or Kallmann syndrome (e.g., Dwyer_2022), however without strong evidence for causality. These reports do not provide conclusions about association of the variant with Hypogonadotropic Hypogonadism 15 With Or Without Anosmia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments, classifying the variant as uncertain significance (n = 1), likely benign (n = 1), and benign (n = 1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.