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

gnomAD frequency: 0.00003  dbSNP: rs748057401

Total submissions: 8

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
Labcorp Genetics (formerly Invitae), Labcorp	RCV001856978	SCV002258841	likely pathogenic	Bifunctional peroxisomal enzyme deficiency; Perrault syndrome	2024-07-29	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
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000671323	SCV005399833	likely pathogenic	Bifunctional peroxisomal enzyme deficiency	2024-09-20	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely 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 arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (4 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (2 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated (3R)-hydroxyacyl-CoA dehydrogenase domain (UniProt). (I) 0703 - Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. Two alternate changes at this residue have been reported as pathogenic/likely pathogenic in ClinVar. (SP) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. This variant has been reported twice in ClinVar as likely pathogenic and twice as a variant of unknown significance. It has also been reported in the literature in two unrelated individuals with D-bifunctional protein deficiency (PMIDs: 34732400, 34534157). (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV005001988	SCV005626394	likely pathogenic	Perrault syndrome 1		criteria provided, single submitter	research	A known missense variant, c.743G>A in exon 11 of HSD17B4 (Schon et al., 2021; ClinVar ID: VCV000430263.14) was observed in homozygous state in proband. Sanger validation and segregation analysis showed that the variant was observed in homozygous state in him and heterozygous state in his parents. This variant is observed in heterozygous state in 29 individuals in gnomAD database (v4.1.0) and absent in our in-house data of 3447 exomes. This variant is absent in homozygous state in gnomAD and our in-house data of 3447 exomes
PreventionGenetics, part of Exact Sciences	RCV004541543	SCV004765905	uncertain significance	HSD17B4-related disorder	2023-11-16	no assertion criteria provided	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.