Submissions for variant NM_000414.4(HSD17B4):c.1566T>A (p.Ser522Arg)

gnomAD frequency: 0.00005  dbSNP: rs184492796

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000217919	SCV000269159	benign	not specified	2015-12-04	criteria provided, single submitter	clinical testing	p.Ser547Arg in exon 19 of HSD17B4: This variant is not expected to have clinical significance because it has been identified in 0.49% (42/8640) of East Asian ch romosomes, including 1 homozygote individual, by the Exome Aggregation Consortiu m (ExAC, http://exac.broadinstitute.org; dbSNP rs184492796).
Illumina Laboratory Services, Illumina	RCV000359350	SCV000452133	likely benign	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Laboratory Services, Illumina	RCV000264639	SCV000452134	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000906457	SCV001051092	benign	Bifunctional peroxisomal enzyme deficiency; Perrault syndrome	2024-01-30	criteria provided, single submitter	clinical testing
GeneDx	RCV001580473	SCV001817892	likely benign	not provided	2020-09-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000217919	SCV005395643	likely benign	not specified	2024-09-05	criteria provided, single submitter	clinical testing	Variant summary: HSD17B4 c.1566T>A (p.Ser522Arg) results in a non-conservative amino acid change located in the MaoC-like dehydratase domain (IPR002539) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00044 in 250906 control chromosomes, predominantly at a frequency of 0.0059 within the East Asian subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in HSD17B4 causing D-Bifunctional Protein Deficiency phenotype (0.003). To our knowledge, no occurrence of c.1566T>A in individuals affected with D-Bifunctional Protein Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 226666). Based on the evidence outlined above, the variant was classified as likely benign.
Natera, Inc.	RCV000264639	SCV001458670	benign	Bifunctional peroxisomal enzyme deficiency	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004541308	SCV004788914	likely benign	HSD17B4-related disorder	2020-05-11	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).