Submissions for variant NM_000414.4(HSD17B4):c.1471G>A (p.Ala491Thr)

dbSNP: rs28943591

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000175136	SCV000226571	likely benign	not specified	2015-03-30	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000175136	SCV000269157	benign	not specified	2014-11-24	criteria provided, single submitter	clinical testing	Ala516Thr in exon 18 of HSD17B4: This variant is not expected to have clinical s ignificance because it has been identified in 0.6% (48/8596) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs28943591).
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224951	SCV000280844	likely benign	not provided	2015-08-19	criteria provided, single submitter	clinical testing	Converted during submission to Likely benign.
Illumina Laboratory Services, Illumina	RCV000298832	SCV000452129	likely benign	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 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	RCV000353669	SCV000452130	likely benign	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 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.
GeneDx	RCV000175136	SCV000714003	benign	not specified	2017-12-07	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae	RCV001084433	SCV001113671	benign	Bifunctional peroxisomal enzyme deficiency; Perrault syndrome	2024-01-31	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000224951	SCV001144222	likely benign	not provided	2019-07-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000224951	SCV001154490	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	HSD17B4: BP4, BS2
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000224951	SCV001472252	benign	not provided	2023-10-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000175136	SCV002570591	benign	not specified	2022-07-27	criteria provided, single submitter	clinical testing	Variant summary: HSD17B4 c.1471G>A (p.Ala491Thr) results in a non-conservative amino acid change located in the MaoC-like dehydratase domain (IPR002539) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0034 in 251252 control chromosomes in the gnomAD database, including 3 homozygotes. The observed variant frequency is approximately 1.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in HSD17B4 causing D-Bifunctional Protein Deficiency phenotype (0.003), strongly suggesting that the variant is benign. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine ClinVar submitters (evaluation after 2014) cite the variant as benign (n=4) and likely benign (n=5). Based on the evidence outlined above, the variant was classified as benign.
GenomeConnect, ClinGen	RCV000509557	SCV000607089	not provided	Bifunctional peroxisomal enzyme deficiency; Perrault syndrome 1		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Natera, Inc.	RCV000353669	SCV001457298	benign	Bifunctional peroxisomal enzyme deficiency	2020-01-12	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000224951	SCV001963293	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000224951	SCV001969210	likely benign	not provided		no assertion criteria provided	clinical testing