ClinVar Miner

Submissions for variant NM_000197.2(HSD17B3):c.277+4A>T (rs201115371)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000190594 SCV000245621 pathogenic Testosterone 17-beta-dehydrogenase deficiency 2014-12-24 criteria provided, single submitter clinical testing The c.277+4A>T variant in HSD17B3 has been reported in 12 patients with male pse udohermaphroditism (4 homozygotes and 8 compound heterozygotes) and segregated w ith disease in 2 affected relatives (Boehmer 1999, Castro 2012). This variant is located in the 5' splice region. Studies on RNA isolated from patients demonstr ated that the c.277+4A>T variant leads to impaired splicing and reduced HSD17B3 transcript levels (Boehmer 1999). This variant has also been identified 0.04% (4 5/116,062) of chromosomes by the Exome Aggregation Consortium (ExAC, http://exac; dbSNP 201115371). Although this variant has been seen in th e general population, its frequency is low enough to be consistent with a recess ive carrier frequency. In summary, the c.277+4A>T variant meets our criteria to be classified as pathogenic for 17 beta-hydroxysteroid dehydrogenase 3 deficienc y in an autosomal recessive manner based upon its identification and segregation in affected individuals, low frequency in controls, and functional evidence.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000224578 SCV000281003 pathogenic not provided 2017-10-05 criteria provided, single submitter clinical testing
GeneDx RCV000224578 SCV000322435 pathogenic not provided 2017-11-13 criteria provided, single submitter clinical testing The c.277+4A>T pathogenic variant in the HSD17B3 gene has been reported previously in multiple individuals with 17-beta hydroxysteroid dehydrogenase 3 deficiency in the homozygous state, as well as in the heterozygous state in the presence of a second HSD17B3 variant (Boehmer et al., 1999; Phelan et al, 2015). This splice site variant destroys the canonical splice donor site in intron 3. RNA analysis of the c.277+4A>T variant indicates that it results in loss-of-function (Boehmer et al., 1999). The c.277+4A>T variant is observed in 89/126556 (0.07%) alleles from individuals of non-Finnish European background in large population cohorts (Lek et al., 2016). We interpret c.277+4A>T as a pathogenic variant.
Ambry Genetics RCV000623449 SCV000741009 pathogenic Inborn genetic diseases 2015-07-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Illumina Clinical Services Laboratory,Illumina RCV000190594 SCV000916272 pathogenic Testosterone 17-beta-dehydrogenase deficiency 2018-09-07 criteria provided, single submitter clinical testing Across a selection of the available literature, the HSD17B3 c.277+4A>T variant has been identified in a homozygous state in at least nine probands and in a compound heterozygous state in eleven probands (Andersson et al. 1996; Boehmer et al. 1999; Mains et al. 2008; Castro et al. 2012). Additionally, Boehmer et al. (1999) performed transcript analysis of a homozygous patient that showed the c.277+4A>T variant results in skipping of exon three of HSD17B3. The c.277+4A>T variant was absent from 200 control subjects and is reported at a frequency of 0.000703 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the evidence, the c.277+4A>T variant is classified as pathogenic for 17-beta-hydroxysteroid dehydrogenase III deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000582593 SCV000692116 pathogenic Pseudohermaphroditism 2015-07-31 no assertion criteria provided clinical testing

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