Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003324315 | SCV004030083 | pathogenic | Testosterone 17-beta-dehydrogenase deficiency | 2023-07-17 | criteria provided, single submitter | clinical testing | Variant summary: HSD17B3 c.277G>A (p.Glu93Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Four predict the variant weakens a canonical 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing in vitro, as well as finding aberrant transcripts in a patient homozygous with the variant (Zhu_2023). The variant allele was found at a frequency of 4e-06 in 251000 control chromosomes (gnomAD). c.277G>A has been reported in the literature in multiple individuals affected with Testosterone 17-beta-dehydrogenase deficiency (Ozen_2017, Zhu_2023, Ata_2021, Yu_2018), and some were reported as compound heterozygous with another pathogenic variant. 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 of the missense change, finding no effect on conversion of androstenedione to testosterone, suggesting the variant exerts its effect as an exonic splicing variant rather than a missense variant (Zhu_2023). The following publications have been ascertained in the context of this evaluation (PMID: 27898418, 36154887, 33516834, 29397602). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. |
| Labcorp Genetics |
RCV003561300 | SCV004296027 | pathogenic | not provided | 2023-09-12 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change is associated with altered splicing resulting in multiple RNA products (PMID: 36154887). Experimental studies have shown that this missense change does not substantially affect HSD17B3 function (PMID: 36154887). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 2577238). This missense change has been observed in individual(s) with clinical features of 17-beta hydroxysteroid dehydrogenase 3 deficiency (PMID: 27898418, 29397602, 36154887). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs753360928, gnomAD 0.003%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 93 of the HSD17B3 protein (p.Glu93Lys). This variant also falls at the last nucleotide of exon 3, which is part of the consensus splice site for this exon. |