ClinVar Genomic variation as it relates to human health

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 270 of the HSD3B2 protein (p.Ile270Thr). This variant is present in population databases (rs75429891, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with HSD3B2-related conditions. ClinVar contains an entry for this variant (Variation ID: 874298). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Variant summary: HSD3B2 c.809T>C (p.Ile270Thr) results in a non-conservative amino acid change located in the 3-beta hydroxysteroid dehydrogenase/isomerase domain (IPR00225) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00046 in 251256 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in HSD3B2 causing Congenital Adrenal Hyperplasia (0.00046 vs 0.0013), allowing no conclusion about variant significance. c.809T>C has been reported in the literature in at least one individual affected with clinical features of Congenital Adrenal Hyperplasia. However, this report does not provide unequivocal conclusions about association of the variant with Congenital Adrenal Hyperplasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 30668521). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014; all submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

HSD3B2: PM2, BP4

The HSD3B2 c.809T>C variant is predicted to result in the amino acid substitution p.Ile270Thr. This variant was reported in an individual with hypogonadism in a disorder of sex development study, but the clinical significance was unknown (Hughes et al. 2019. PubMed ID: 30668521). This variant is reported in 0.084% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.