Submissions for variant NM_000414.4(HSD17B4):c.743G>A (p.Arg248His)

gnomAD frequency: 0.00003  dbSNP: rs748057401

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000493335	SCV000583034	likely pathogenic	not provided	2022-05-02	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27535533)
Counsyl	RCV000671323	SCV000796285	uncertain significance	Bifunctional peroxisomal enzyme deficiency	2017-12-15	criteria provided, single submitter	clinical testing
Invitae	RCV001856978	SCV002258841	likely pathogenic	Bifunctional peroxisomal enzyme deficiency; Perrault syndrome	2023-12-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 248 of the HSD17B4 protein (p.Arg248His). This variant is present in population databases (rs748057401, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of HSD17B4-related conditions (PMID: 34732400). ClinVar contains an entry for this variant (Variation ID: 430263). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on HSD17B4 protein function. This variant disrupts the p.Arg248 amino acid residue in HSD17B4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16385454, 23308274, 27528516). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282178	SCV002572320	uncertain significance	not specified	2023-12-15	criteria provided, single submitter	clinical testing	Variant summary: HSD17B4 c.743G>A (p.Arg248His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 250756 control chromosomes. c.743G>A has been reported in the literature in at least one individual affected with a multisystem progressive disorder, where it was found in compound heterozygosity with a truncating variant (c.590_597dupGATCACGG; p.Met200fs) (Schon_2021). These data alone do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, another missense variant affecting the same amino acid (p.Arg248Cys) has been classified as pathogenic by our laboratory in relation to D-Bifunctional Protein Deficiency. The following publication has been ascertained in the context of this evaluation (PMID: 34732400). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Two classified the variant as likely pathogenic, and one classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Baylor Genetics	RCV000671323	SCV004192365	likely pathogenic	Bifunctional peroxisomal enzyme deficiency	2024-01-21	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004541543	SCV004765905	uncertain significance	HSD17B4-related disorder	2023-11-16	criteria provided, single submitter	clinical testing	The HSD17B4 c.743G>A variant is predicted to result in the amino acid substitution p.Arg248His. This variant was reported in a compound heterozygous individual with a mitochondrial disorder (Family 66, Table 2, Schon et al 2021. PubMed ID: 34732400). A different variant impacting the same amino acid residue (p.Arg248Cys) has been reported in the homozygous and compound heterozygous state in individuals with D-bifunctional protein deficiency (Mehtälä et al. 2013. PubMed ID: 23308274; Ferdinandusse et al. 2005. PubMed ID: 16385454). This variant is reported in 0.0035% of alleles in individuals of European (Non-Finnish) descent in gnomAD. While this variant could be pathogenic, at this time its clinical significance is interpreted as uncertain due to the absence of conclusive functional and genetic evidence.