Submissions for variant NM_000414.4(HSD17B4):c.622+5G>A

gnomAD frequency: 0.00006  dbSNP: rs536487449

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000841012	SCV000982968	likely benign	not provided	2019-05-06	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001157567	SCV001319155	uncertain significance	Perrault syndrome 1	2018-01-12	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	RCV001157568	SCV001319156	uncertain significance	Bifunctional peroxisomal enzyme deficiency	2018-01-12	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.
Invitae	RCV002536126	SCV003448484	uncertain significance	Bifunctional peroxisomal enzyme deficiency; Perrault syndrome	2022-06-20	criteria provided, single submitter	clinical testing	This sequence change falls in intron 8 of the HSD17B4 gene. It does not directly change the encoded amino acid sequence of the HSD17B4 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs536487449, gnomAD 0.01%). 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: 681160). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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.
PreventionGenetics, part of Exact Sciences	RCV004538156	SCV004115165	uncertain significance	HSD17B4-related disorder	2023-08-07	criteria provided, single submitter	clinical testing	The HSD17B4 c.622+5G>A variant is predicted to interfere with splicing. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-118814721-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Natera, Inc.	RCV001157568	SCV001457291	uncertain significance	Bifunctional peroxisomal enzyme deficiency	2019-11-11	no assertion criteria provided	clinical testing