ClinVar Miner

Submissions for variant NM_000198.4(HSD3B2):c.707T>C (p.Leu236Ser) (rs35887327)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America 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.
Invitae RCV000965562 SCV001112832 benign not provided 2019-12-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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.

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