ClinVar Miner

Submissions for variant NM_000414.4(HSD17B4):c.46G>A (p.Gly16Ser) (rs137853096)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 8
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Praxis fuer Humangenetik Tuebingen RCV000415821 SCV000493593 likely pathogenic not provided 2016-07-31 criteria provided, single submitter clinical testing
Counsyl RCV000008094 SCV000485152 likely pathogenic Bifunctional peroxisomal enzyme deficiency 2015-12-17 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000415821 SCV000331675 pathogenic not provided 2017-06-19 criteria provided, single submitter clinical testing
GeneDx RCV000415821 SCV000617161 pathogenic not provided 2018-05-21 criteria provided, single submitter clinical testing The G16S variant in the HSD17B4 gene has been reported previously in the homozygous and compound heterozygous states in multiple unrelated individuals with HSD17B4-related disorders (van Grunsven et al., 1998; Konkolova et al., 2015; Demain et al., 2016). Although not present in the homozygous state, the G16S variant is observed in 25/66512 (0.038%) alleles from individuals of non-Finnish European background in the ExAC dataset (Lek et al., 2016). The G16S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs within the NAD nucleotide binding region at a position that is conserved across species. In vitro assays in yeast demonstrate that G16S results in an inactive 3-hydroxyacyl-CoA dehydrogenase component of D-bifunctional protein (van Grunsven et al., 1998). We interpret G16S as a pathogenic variant.
Illumina Clinical Services Laboratory,Illumina RCV000779455 SCV000916080 pathogenic HSD17B4-Related Disorders 2018-10-16 criteria provided, single submitter clinical testing The HSD17B4 c.46G>A (p.Gly16Ser) missense variant has been reported in at least five studies and has been identified in at least 29 probands with peroxisomal bifunctional enzyme deficiency, including in 26 individuals in a homozygous state and in three individuals in a compound heterozygous state (van Grunsven et al. 1998; van Grunsven et al. 1999; Ferdinandusse et al. 2006; Konkoľová et al. 2015). The variant was also identified in a compound heterozygous state with a missense variant in one individual with Perrault syndrome (Demain et al. 2016). Control data are unavailable for this variant, which is reported at a frequency of 0.000391 in the European (non-Finnish) population of the Genome Aggregation Database. The p.Gly16Ser variant is located at a conserved residue in a loop affecting the binding site of the dehydrogenase region of the protein. Functional studies in yeast expressing the variant and wild type protein showed loss of 3-hydroxyacyl-CoA dehydrogenase activity, but did not affect the enoyl-CoA hydratase activity (van Grunsven et al. 1998). Based on the collective evidence, the p.Gly16Ser variant is classified as pathogenic for HSD17B4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Integrated Genetics/Laboratory Corporation of America RCV000008094 SCV000696691 pathogenic Bifunctional peroxisomal enzyme deficiency 2016-09-02 criteria provided, single submitter clinical testing Variant summary: The c.46G>A (p.Gly16Ser) in HSD17B4 gene is a missense change that involves a conserved nucleotide and 5/5 in silico tools predict deleterious outcome. The variant of interest is located within the dehydrogenase domain and mutations were proven to lead to inactivation of the 3-hydroxyacyl-CoA dehydrogenase component. The variant is present in the large control population dataset of ExAC at a low frequency 0.0002 (27/121004 chrs tested), which does not exceed the maximal expected frequency of a pathogenic allele (0.0029) in this gene. The variant has been reported in multiple affected individuals in homozygous and compound heterozygous state from and was proven to segregate with the disease reputable databases/clinical laboratories classified this variant as Pathogenic. The c.46G>A is widely accepted to be one of the most common pathogenic variants to cause D-BPD. Taken together, the variant was classified as Pathogenic.
Invitae RCV000688945 SCV000816576 likely pathogenic Bifunctional peroxisomal enzyme deficiency; Perrault syndrome 2018-12-24 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 16 of the HSD17B4 protein (p.Gly16Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs137853096, ExAC 0.04%). This variant has been reported to be homozygous or in combination with other HSD17B4 variants as compound heterozygous in multiple individuals affected with D-bifunctional protein deficiency (PMID: 16385454, 9482850, 25967389). It has also been reported as compound heterozygous in an individual affected with hypotonia, seizures, and suspicion of muscular dystrophy (PMID: 27290639) and an individual with Perrault syndrome (PMID: 26970254). ClinVar contains an entry for this variant (Variation ID: 7655). Experimental studies have shown that this missense change results in the loss of 3-hydroxyacyl-CoA dehydrogenase activity but does not affect enoyl-CoA hydratase activity in vivo (PMID: 9482850). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
OMIM RCV000008094 SCV000028299 pathogenic Bifunctional peroxisomal enzyme deficiency 1999-01-01 no assertion criteria provided literature only

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.