ClinVar Miner

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

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000415821 SCV000331675 pathogenic not provided 2017-06-19 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000415821 SCV000493593 likely pathogenic not provided 2016-07-01 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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 pathogenic Bifunctional peroxisomal enzyme deficiency; Perrault syndrome 2020-10-11 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, 10497229, 10419023). 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. For these reasons, this variant has been classified as Pathogenic.
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.
Baylor Genetics RCV000008094 SCV001162969 pathogenic Bifunctional peroxisomal enzyme deficiency criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000008094 SCV001194090 likely pathogenic Bifunctional peroxisomal enzyme deficiency 2019-12-26 criteria provided, single submitter clinical testing NM_000414.3(HSD17B4):c.46G>A(G16S) is classified as likely pathogenic in the context of D-bifunctional protein deficiency. Sources cited for classification include the following: PMID 16385454, 9482850, 10419023 and 10497229. Classification of NM_000414.3(HSD17B4):c.46G>A(G16S) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000415821 SCV001251900 pathogenic not provided 2020-05-03 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001197145 SCV001367781 pathogenic Perrault syndrome 1 2019-05-07 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP3.
UNC Molecular Genetics Laboratory,University of North Carolina at Chapel Hill RCV000008094 SCV001423843 likely pathogenic Bifunctional peroxisomal enzyme deficiency criteria provided, single submitter research HSD17B4 c.46G>A is predicted to result in a single amino acid change from glycine to serine. It is the most common pathogenic variant associated with DBP deficiency and has been reported in over 30 individuals with DBP deficiency (PMID:9482850; 16385454; 25967389; 26970254).
OMIM RCV000008094 SCV000028299 pathogenic Bifunctional peroxisomal enzyme deficiency 1999-01-01 no assertion criteria provided literature only

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