Submissions for variant NM_000198.4(HSD3B2):c.707T>C (p.Leu236Ser)

gnomAD frequency: 0.01309  dbSNP: rs35887327

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000030039	SCV000052694	benign	not specified	2020-07-14	criteria provided, single submitter	curation	Variant Summary: HSD3B2 c.707T>C (p.Leu236Ser) results in a non-conservative amino acid change located in the 3-beta hydroxysteroid dehydrogenase/isomerase domain (IPR002225) 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 0.003 in 250862 control chromosomes, predominantly at a frequency of 0.042 within the African or African-American subpopulation in the gnomAD database, including 15 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 33 fold of the estimated maximal expected allele frequency for a pathogenic variant in HSD3B2 causing Congenital Adrenal Hyperplasia phenotype (0.0013), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.707T>C has been reported in the literature in individuals affected with nonsalt wasting form of classical 3 beta HSD deficiency, hyperandrogenic adolescents, children with primary public hair and autoimmune Addison's disease patients (Nayak_1998, Moisan_1999, Aslaksen_2019). These reports however, do not provide unequivocal conclusions about association of the variant with Congenital Adrenal Hyperplasia. At least one publication reports experimental evidence evaluating an impact on protein function and the results showed no damaging effect of this variant on the kinetic properties and activity of 3 beta hydroxysteroid dehydrogenase enzyme (Moisan_1999). Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=1) or benign (n=1). Based on the evidence outlined above, the variant was re-classified as benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000965562	SCV001112832	benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001097134	SCV001253388	uncertain significance	3 beta-Hydroxysteroid dehydrogenase deficiency	2017-04-27	criteria provided, single submitter	clinical testing	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.
GeneDx	RCV000965562	SCV001774392	likely benign	not provided	2020-08-24	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 31611844, 9719627, 20981092, 10599696, 22995991, 11196452)
Natera, Inc.	RCV001097134	SCV002094672	benign	3 beta-Hydroxysteroid dehydrogenase deficiency	2019-11-14	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003964818	SCV004795183	benign	HSD3B2-related disorder	2019-07-02	no assertion criteria provided	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).