Submissions for variant NM_000414.4(HSD17B4):c.1280C>T (p.Ala427Val)

gnomAD frequency: 0.00006  dbSNP: rs28943590

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000727234	SCV000603970	uncertain significance	not provided	2020-03-23	criteria provided, single submitter	clinical testing	The p.Ala452Val variant (rs28943590) has not been reported in the medical literature, or gene specific variation databases. This variant is listed in the Exome Aggregation Consortium Browser with a Latino population frequency of 0.3 percent (identified on 33 out of 11,186 chromosomes). The alanine at position 452 is moderately conserved (considering 12 species) (Alamut v2.8.1) and computational analyses of the effects of the p.Ala452Val variant on protein structure and function provide conflicting results (SIFT: tolerated, MutationTaster: disease causing, PolyPhen-2: benign). Altogether, there is not enough evidence to classify the p.Ala452Val variant with certainty.
Invitae	RCV001083581	SCV000636108	likely benign	Bifunctional peroxisomal enzyme deficiency; Perrault syndrome	2024-01-25	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000727234	SCV000706824	uncertain significance	not provided	2018-02-13	criteria provided, single submitter	clinical testing
GeneDx	RCV000727234	SCV000727311	benign	not provided	2020-10-28	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 28649525, 22864515)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000506112	SCV001365869	uncertain significance	not specified	2019-08-27	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Ala452Val variant in HSD17B4 has not been previously reported in individuals with Perrault syndrome, but has been identified in 0.2% (83/35360) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, while the clinical significance of this variant is uncertain, its frequency suggests that it is more likely to be benign. ACMG/AMP Criteria applied: BS1_Supporting.
PreventionGenetics, part of Exact Sciences	RCV004541583	SCV004776417	likely benign	HSD17B4-related disorder	2022-07-08	criteria provided, single submitter	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).