Submissions for variant NM_000414.4(HSD17B4):c.1517G>A (p.Arg506His)

dbSNP: rs1554068136

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000670512	SCV000795371	uncertain significance	Bifunctional peroxisomal enzyme deficiency	2017-11-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000670512	SCV002600631	likely pathogenic	Bifunctional peroxisomal enzyme deficiency	2022-10-21	criteria provided, single submitter	clinical testing	Variant summary: HSD17B4 c.1517G>A (p.Arg506His) results in a non-conservative amino acid change located in the MaoC-like dehydratase domain (IPR002539) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250870 control chromosomes (gnomAD). c.1517G>A (p.R506H) has been reported in the literature in at least one homozygous individual affected with D-Bifunctional Protein Deficiency (Ferdinandusse_2006). In addition, another variant (R506C) at the same residue was found in three homozygous patients affected with DBP II (Ferdinandusse_2006) and this variant has been classified as DV in our lab, suggesting this residue is clinical and fuctional important. These data indicate that the variant may be associated with disease. At least one publication reports the hydratase activity was abolished by this variant (Tsuchida_2012). One ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000670512	SCV003921895	pathogenic	Bifunctional peroxisomal enzyme deficiency	2022-02-23	criteria provided, single submitter	clinical testing	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) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (4 heterozygotes, 0 homozygotes). (I) 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 MaoC-like domain (DECIPHER). (I) 0703 - Another missense variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. The p.(Arg506Cys) variant has been reported in three individuals with DBP deficiency (PMID: 16385454), and as likely pathogenic/pathogenic in ClinVar. (SP) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual. It has been reported as homozygous in an individual with D-bifunctional protein deficiency (PMID: 16385454). The variant has also been reported as a VUS in ClinVar however no further evidence was provided. (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1006 - Clinically accredited laboratory assay shows abnormal function of product not specific to the gene. VLCFA assay showed abnormal result in this individual (personal communication). (SP) 1101 - Very strong and specific phenotype match for this individual. (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_000414.3:c.31dupG, p.(Val11Glyfs*30)) in a recessive disease. (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Baylor Genetics	RCV000670512	SCV004192389	likely pathogenic	Bifunctional peroxisomal enzyme deficiency	2023-08-24	criteria provided, single submitter	clinical testing
Invitae	RCV003767986	SCV004569604	likely pathogenic	Bifunctional peroxisomal enzyme deficiency; Perrault syndrome	2023-09-12	criteria provided, single submitter	clinical testing	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. This variant disrupts the p.Arg506 amino acid residue in HSD17B4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16385454, 25967389). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects HSD17B4 function (PMID: 22864515). 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. ClinVar contains an entry for this variant (Variation ID: 554817). This missense change has been observed in individual(s) with D-bifunctional protein deficiency (PMID: 16385454). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 506 of the HSD17B4 protein (p.Arg506His).