Submissions for variant NM_000414.4(HSD17B4):c.1210-1G>A

dbSNP: rs1554065671

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000666626	SCV000790948	likely pathogenic	Bifunctional peroxisomal enzyme deficiency	2017-04-18	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001387366	SCV001587980	pathogenic	Bifunctional peroxisomal enzyme deficiency; Perrault syndrome	2023-04-06	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 13 of the HSD17B4 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in HSD17B4 are known to be pathogenic (PMID: 11810648, 16385454, 20673864). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of D-bifunctional protein deficiency (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 551541). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000666626	SCV003934503	likely pathogenic	Bifunctional peroxisomal enzyme deficiency	2025-01-30	criteria provided, single submitter	clinical testing	Variant summary: HSD17B4 c.1210-1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing and loss of HSD17B4 function. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251028 control chromosomes (gnomAD). c.1210-1G>A has been reported in individuals affected with HSD17B4-related conditions (Internal testing, Gagnon_2023 ) These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications has been ascertained in the context of this evaluation (PMID: 36649687). ClinVar contains an entry for this variant (Variation ID: 551541). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV000666626	SCV005059740	pathogenic	Bifunctional peroxisomal enzyme deficiency	2024-02-27	criteria provided, single submitter	clinical testing