Submissions for variant NM_000414.4(HSD17B4):c.1992G>C (p.Trp664Cys)

gnomAD frequency: 0.00001  dbSNP: rs752858179

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000756251	SCV000884001	uncertain significance	not provided	2018-04-12	criteria provided, single submitter	clinical testing	The p.Trp689Cys variant (rs752858179) has not been reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the Genome Aggregation Database (gnomAD) with a frequency of 0.03 percent in the Latino population (identified on 10 out of 33,492 chromosomes). The tryptophan at position 689 is highly conserved up to zebrafish considering 12 species (Alamut v2.11) and computational analyses of the effects of the p.Trp689Cys variant on protein structure and function indicate a deleterious effect (SIFT: damaging, PolyPhen-2: probably damaging). Altogether, there is not enough evidence to classify the p.Trp689Cys variant with certainty.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002533784	SCV003261928	uncertain significance	Bifunctional peroxisomal enzyme deficiency; Perrault syndrome	2022-08-19	criteria provided, single submitter	clinical testing	This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 664 of the HSD17B4 protein (p.Trp664Cys). This variant is present in population databases (rs752858179, gnomAD 0.03%). 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: 618167). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155302	SCV003845160	uncertain significance	not specified	2023-02-24	criteria provided, single submitter	clinical testing	Variant summary: HSD17B4 c.1992G>C (p.Trp664Cys) results in a non-conservative amino acid change located in the SCP2 sterol-binding domain (IPR003033) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251212 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in HSD17B4 causing D-Bifunctional Protein Deficiency (4e-05 vs 0.003), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1992G>C in individuals affected with D-Bifunctional Protein Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. Three submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV000756251	SCV005388408	uncertain significance	not provided	2025-02-16	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Natera, Inc.	RCV001835947	SCV002075428	uncertain significance	Bifunctional peroxisomal enzyme deficiency	2019-10-28	no assertion criteria provided	clinical testing