ClinVar Genomic variation as it relates to human health

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.

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.

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP3.

DNA sequence analysis of the HSD17B4 gene demonstrated a sequence change, c.46G>A, in exon 1 that results in an amino acid change, p.Gly16Ser. This sequence change has been reported in multiple individuals with D-bifunctional protein deficiency in both homozygous and compound heterozygous state with another variant (PMID: 25967389, PMID: 9482850, PMID:16385454). It has also been identified in a patient with Perrault syndrome who presented with bilateral progressive sensorineural hearing loss, premature ovarian insufficiency and progressive cerebellar ataxia (PMID: 26970254). This sequence change has been described in the gnomAD database with a low population frequency of 0.038% in non-Finnish European subpopulation; however, it has not been observed in homozygous state in any individuals (dbSNP rs137853096). The p.Gly16Ser change affects a highly conserved amino acid residue located in a domain of the HSD17B4 protein that is known to be functional. This sequence change is located in an important loop of the Rossman fold which forms the binding site for the essential cofactor NAD+ and is predicted to alter the binding site. Expression studies in yeast showed that this mutant causes loss of the 3-hydroxyacyl-CoA dehydrogenase activity, an essential component of d-bifunctional protein (PMID: 9482850). The p.Gly16Ser substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). These collective evidences indicate that this sequence change is pathogenic.

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.020%). While this variant results in missense change, protein truncation variants are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 10419023 , 10497229 , 9482850). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.95; 3Cnet: 0.95). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 25967389 , 9482850). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

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.

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).

PS3, PM3_Strong, PP3

Identified as compund heterozygous with NM_000414.4:c.53G>T. Criteria applied: PM3_VSTR,PM2_SUP,PP3

Published functional studies demonstrate variant inactivates the 3-hydroxyacyl-CoA dehydrogenase component of the D-bifunctional protein (van Grunsven et al., 1998); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 23308274, 11165012, 25967389, 10343282, 9482850, 26970254, 27290639, 27650058, 31980526, 34906502, 34426522, 34493867)

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 16 of the HSD17B4 protein (p.Gly16Ser). This variant is present in population databases (rs137853096, gnomAD 0.04%). This missense change has been observed in individuals with D-bifunctional protein deficiency (PMID: 9482850, 16385454, 25967389). ClinVar contains an entry for this variant (Variation ID: 7655). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt HSD17B4 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects HSD17B4 function (PMID: 9482850, 10419023, 10497229). For these reasons, this variant has been classified as Pathogenic.

HSD17B4: PM3:Very Strong, PM2, PP3, PP4, PS3:Supporting

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with D-bifunctional protein deficiency (MIM#261515) and Perrault syndrome 1 (MIM#233400). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to serine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (57 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated short chain dehydrogenase domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic and likely pathogenic by multiple clinical laboratories in ClinVar. This variant has also been previously described as pathogenic in multiple patients with D-bifunctional protein deficiency and Perrault syndrome (ClinVar, PMID: 9482850, 25967389, 26970254). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

The HSD17B4 c.46G>A variant is predicted to result in the amino acid substitution p.Gly16Ser. This variant is known to be causative for D-bifunctional protein deficiency and Perrault syndrome, with functional experiments showing this results in inactive dehydrogenase enzymatic activity (van Grunsven et al. 1998. PubMed ID: 9482850; Demain et al. 2016. PubMed ID: 26970254; Pronicka et al. 2016. PubMed ID: 27290639). This variant is reported in 0.038% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.

The most common pathogenic variant causing D-bifunctional protein deficiency.