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

dbSNP: rs749532705

Total submissions: 6

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	2024-02-24	criteria provided, single submitter	clinical testing
Invitae	RCV001040699	SCV001204288	pathogenic	Bifunctional peroxisomal enzyme deficiency; Perrault syndrome	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (Splice site) in the HSD17B4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HSD17B4 are known to be pathogenic (PMID: 11810648, 16385454, 20673864). This variant is present in population databases (rs749532705, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with D-bifunctional protein deficiency (PMID: 32904102; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as c.868+1del. ClinVar contains an entry for this variant (Variation ID: 632857). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000780346	SCV001984801	likely pathogenic	Bifunctional peroxisomal enzyme deficiency	2020-09-04	criteria provided, single submitter	clinical testing	This frameshifting variant in exon 12 of 25 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has not been previously reported or functionally characterized in the literature to our knowledge. It is present in the heterozygous state in the gnomAD population database at a frequency of 0.002% (4/250944) and thus is presumed to be rare. Based on the available evidence, the c.943+1del variant is classified as Likely Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002487606	SCV002786645	likely pathogenic	Bifunctional peroxisomal enzyme deficiency; Perrault syndrome 1	2022-01-14	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004527810	SCV004105463	likely pathogenic	HSD17B4-related disorder	2023-01-04	criteria provided, single submitter	clinical testing	The HSD17B4 c.868+1delG variant is predicted to result in a deletion affecting a canonical splice site. This variant was reported as pathogenic in a patient with D-bifunctional protein deficiency (Landau et al. 2020. PubMed ID: 32904102). This variant is reported in 0.012% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-118829640-AG-A). This variant is interpreted as likely pathogenic.