Submissions for variant NM_000198.4(HSD3B2):c.849del (p.Arg282_Trp283insTer)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002302452	SCV002598579	likely pathogenic	Congenital adrenal hyperplasia	2022-09-12	criteria provided, single submitter	clinical testing	Variant summary: HSD3B2 c.849delG (p.Trp283X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Other truncations downstream of this position have been found in association with adrenal hyperplasia and disorders of androgen synthesis in HGMD, suggesting that this region of the protein is clinically relevant. The variant was absent in 251314 control chromosomes. To our knowledge, no occurrence of c.849delG in individuals affected with Congenital Adrenal Hyperplasia and no experimental evidence demonstrating its impact on protein function have 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 likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003718474	SCV004512767	pathogenic	not provided	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp283*) in the HSD3B2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 90 amino acid(s) of the HSD3B2 protein. This variant is not present in population databases (gnomAD no frequency). 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: 1722338). This variant disrupts the C-terminus of the HSD3B2 protein, which has been demonstrated to be critical for enzymatic activity (PMID: 1825279). While functional studies have not been performed to directly test the effect of this variant on HSD3B2 protein function, this suggests that disruption of this region of the protein is causative of disease. This variant disrupts a region of the HSD3B2 protein in which other variant(s) (p.Arg335*) have been determined to be pathogenic (PMID: 18252794, 31006099; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.