Submissions for variant NM_000414.4(HSD17B4):c.1417C>T (p.Arg473Trp)

gnomAD frequency: 0.00016  dbSNP: rs201455193

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000238819	SCV000297067	uncertain significance	not specified	2015-10-16	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000351976	SCV000452127	uncertain significance	Bifunctional peroxisomal enzyme deficiency	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000390048	SCV000452128	uncertain significance	Perrault syndrome 1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Eurofins Ntd Llc (ga)	RCV000733383	SCV000861449	uncertain significance	not provided	2018-05-24	criteria provided, single submitter	clinical testing
Invitae	RCV000819185	SCV000959831	uncertain significance	Bifunctional peroxisomal enzyme deficiency; Perrault syndrome	2022-09-01	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 473 of the HSD17B4 protein (p.Arg473Trp). This variant is present in population databases (rs201455193, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with HSD17B4-related conditions. ClinVar contains an entry for this variant (Variation ID: 252564). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Genome-Nilou Lab	RCV000351976	SCV001737263	uncertain significance	Bifunctional peroxisomal enzyme deficiency	2021-05-18	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002487109	SCV002793636	uncertain significance	Bifunctional peroxisomal enzyme deficiency; Perrault syndrome 1	2021-11-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002518512	SCV003728824	uncertain significance	Inborn genetic diseases	2022-11-03	criteria provided, single submitter	clinical testing	The c.1417C>T (p.R473W) alteration is located in exon 16 (coding exon 16) of the HSD17B4 gene. This alteration results from a C to T substitution at nucleotide position 1417, causing the arginine (R) at amino acid position 473 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000733383	SCV003811248	uncertain significance	not provided	2021-02-28	criteria provided, single submitter	clinical testing
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV000351976	SCV001167498	uncertain significance	Bifunctional peroxisomal enzyme deficiency		no assertion criteria provided	research
Natera, Inc.	RCV000351976	SCV001457297	uncertain significance	Bifunctional peroxisomal enzyme deficiency	2019-12-30	no assertion criteria provided	clinical testing