Submissions for variant NM_000197.2(HSD17B3):c.133C>T (p.Arg45Trp)

gnomAD frequency: 0.00200  dbSNP: rs139084702

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000879849	SCV001022904	likely benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001167680	SCV001330205	uncertain significance	Testosterone 17-beta-dehydrogenase deficiency	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV000879849	SCV001811219	pathogenic	not provided	2023-08-17	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27899157, 34426522, 33503178, 33468338, 30668521, 36606580)
Institute of Human Genetics, University Hospital Muenster	RCV003128420	SCV003804829	uncertain significance	See cases	2023-02-13	criteria provided, single submitter	clinical testing	ACMG categories: PM2,PP2,BP1
PreventionGenetics, part of Exact Sciences	RCV003392673	SCV004120860	uncertain significance	HSD17B3-related condition	2023-01-16	criteria provided, single submitter	clinical testing	The HSD17B3 c.133C>T variant is predicted to result in the amino acid substitution p.Arg45Trp. This variant, in the compound heterozygous condition, was reported in two individuals with hypospadias/ambiguous genitalia (Table S1, Eggers et al 2016. PubMed ID: 27899157; Table 3, Hughes et al 2019. PubMed ID: 30668521). This variant was also reported in two control individuals (Ea et al. 2021. PubMed ID: 33468338). In ClinVar, this variant is interpreted as likely benign/uncertain/likely pathogenic (https://preview.ncbi.nlm.nih.gov/clinvar/variation/708567/). This variant is reported in 0.34% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-99064254-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.