Submissions for variant NM_000198.4(HSD3B2):c.665C>A (p.Pro222Gln)

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	RCV002302451	SCV002598578	pathogenic	Congenital adrenal hyperplasia	2022-09-26	criteria provided, single submitter	clinical testing	Variant summary: HSD3B2 c.665C>A (p.Pro222Gln) results in a non-conservative amino acid change located in the 3-beta hydroxysteroid dehydrogenase/isomerase domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251212 control chromosomes. c.665C>A has been reported in the literature in multiple individuals affected with Congenital Adrenal Hyperplasia. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in loss of normal activity (Moisan_1999). 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 pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003098016	SCV003523347	pathogenic	not provided	2024-10-10	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 222 of the HSD3B2 protein (p.Pro222Gln). This variant is present in population databases (rs765547422, gnomAD 0.006%). This missense change has been observed in individuals with congenital adrenal hyperplasia (PMID: 10599696, 15585552, 21340167, 25211449). ClinVar contains an entry for this variant (Variation ID: 1722337). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt HSD3B2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects HSD3B2 function (PMID: 10599696, 11196452). This variant disrupts the p.Pro222 amino acid residue in HSD3B2. Other variant(s) that disrupt this residue have been observed in individuals with HSD3B2-related conditions (PMID: 12050213), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.