Submissions for variant NM_000198.4(HSD3B2):c.931C>T (p.Gln311Ter)

dbSNP: rs781213951

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001206762	SCV001378086	likely pathogenic	not provided	2024-03-02	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln311*) in the HSD3B2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 62 amino acid(s) of the HSD3B2 protein. This variant is present in population databases (rs781213951, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with congenital adrenal hyperplasia or an unspecified disorder of sexual development (PMID: 27899157, 28207417). ClinVar contains an entry for this variant (Variation ID: 937691). 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003405390	SCV004107500	pathogenic	HSD3B2-related disorder	2023-06-23	criteria provided, single submitter	clinical testing	The HSD3B2 c.931C>T variant is predicted to result in premature protein termination (p.Gln311*). This variant has been reported to be pathogenic for autosomal recessive congenital adrenal hyperplasia (Eggers et al. 2016. PubMed ID: 27899157, Suppl. Table 1; Teasdale et al. 2017. PubMed ID: 28207417; Aslaksen et al. 2019. PubMed ID: 31611844). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-119965055-C-T). Nonsense variants in HSD3B2 are expected to be pathogenic. This variant is interpreted as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003486965	SCV004240800	pathogenic	Congenital adrenal hyperplasia	2023-12-11	criteria provided, single submitter	clinical testing	Variant summary: HSD3B2 c.931C>T (p.Gln311X) results in a premature termination codon, predicted to cause a truncation of the encoded protein, which is a commonly known mechanism for disease. Variants downstream of this position have been classified as pathogenic by our laboratory (example, c.1064G>A p.Trp355X). The variant allele was found at a frequency of 4e-06 in 251330 control chromosomes. c.931C>T has been reported in the literature in at-least one individual affected with Congenital Adrenal Hyperplasia (example, Eggers_2016). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 27899157). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Natera, Inc.	RCV001833816	SCV002094676	likely pathogenic	3 beta-Hydroxysteroid dehydrogenase deficiency	2020-02-28	no assertion criteria provided	clinical testing