Submissions for variant NM_000414.4(HSD17B4):c.742C>T (p.Arg248Cys)

gnomAD frequency: 0.00001  dbSNP: rs969485098

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000409273	SCV000486928	likely pathogenic	Bifunctional peroxisomal enzyme deficiency	2016-09-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000409273	SCV000917534	pathogenic	Bifunctional peroxisomal enzyme deficiency	2018-09-28	criteria provided, single submitter	clinical testing	Variant summary: HSD17B4 c.742C>T (p.Arg248Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function (MutationTaster not captured here due to low p-value). The variant allele was found at a frequency of 8.1e-06 in 245518 control chromosomes (gnomAD). c.742C>T has been reported in the literature in multiple individuals affected with D-Bifunctional Protein Deficiency (Ferdinandusse_2006). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal activity (Mehtala_2013). A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000815715	SCV000956181	pathogenic	Bifunctional peroxisomal enzyme deficiency; Perrault syndrome	2023-12-23	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 248 of the HSD17B4 protein (p.Arg248Cys). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individuals with D-bifunctional protein (DBP) deficiency or Perrault syndrome (PMID: 16385454, 27528516). This variant is also known as p.Arg273Cys. ClinVar contains an entry for this variant (Variation ID: 371366). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects HSD17B4 function (PMID: 23308274). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001840499	SCV002099593	pathogenic	not provided	2022-02-28	criteria provided, single submitter	clinical testing	Published functional studies demonstrated reduced enzyme kinetic performance compared to wild type by enzyme assay, with partial enzyme activity retained (Mehtala et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23308274, 27528516, 29482223, 32528852, 31589614, 34426522, 16385454)
Baylor Genetics	RCV000409273	SCV004192371	pathogenic	Bifunctional peroxisomal enzyme deficiency	2024-03-06	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000409273	SCV002075406	pathogenic	Bifunctional peroxisomal enzyme deficiency	2021-04-09	no assertion criteria provided	clinical testing