ClinVar Miner

Submissions for variant NM_000414.4(HSD17B4):c.868+1del (rs749532705)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780346 SCV000917533 likely pathogenic Bifunctional peroxisomal enzyme deficiency 2018-06-25 criteria provided, single submitter clinical testing Variant summary: HSD17B4 c.868delG (p.Glu290AsnfsX6) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 1.6e-05 in 245702 control chromosomes (gnomAD). To our knowledge, no occurrence of c.868delG in individuals affected with D-Bifunctional Protein Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics RCV000780346 SCV001162970 pathogenic Bifunctional peroxisomal enzyme deficiency criteria provided, single submitter clinical testing
Invitae RCV001040699 SCV001204288 likely pathogenic Bifunctional peroxisomal enzyme deficiency; Perrault syndrome 2020-07-19 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 11 of the HSD17B4 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with HSD17B4-related conditions. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in HSD17B4 are known to be pathogenic (PMID: 11810648, 16385454). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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