Submissions for variant NM_000414.4(HSD17B4):c.420A>T (p.Lys140Asn)

gnomAD frequency: 0.02134  dbSNP: rs28943589

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000221723	SCV000269166	benign	not specified	2014-11-24	criteria provided, single submitter	clinical testing	Lys165Asn in exon 8 of HSD17B4: This variant is not expected to have clinical si gnificance because it has been identified in 6.1% (268/4404) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs28943589).
PreventionGenetics, part of Exact Sciences	RCV000221723	SCV000304080	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000309262	SCV000452109	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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV000368516	SCV000452110	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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Invitae	RCV001084537	SCV000636111	benign	Bifunctional peroxisomal enzyme deficiency; Perrault syndrome	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000221723	SCV000729828	benign	not specified	2017-09-18	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.
Athena Diagnostics Inc	RCV000711976	SCV000842389	benign	not provided	2018-05-24	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000711976	SCV001472909	benign	not provided	2023-11-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000221723	SCV001519622	benign	not specified	2021-03-15	criteria provided, single submitter	clinical testing	Variant summary: HSD17B4 c.420A>T (p.Lys140Asn) results in a non-conservative amino acid change in 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 0.006 in 251368 control chromosomes in the gnomAD database, including 46 homozygotes. The observed variant frequency is approximately 2.0 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 occurrence of c.420A>T in individuals affected with D-Bifunctional Protein Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign.
Natera, Inc.	RCV000309262	SCV001457635	benign	Bifunctional peroxisomal enzyme deficiency	2020-09-16	no assertion criteria provided	clinical testing