Submissions for variant NM_014362.4(HIBCH):c.439-2A>G

dbSNP: rs1180861300

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001378527	SCV001576112	likely pathogenic	Beta-hydroxyisobutyryl-CoA deacylase deficiency	2020-01-13	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 6 of the HIBCH gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in HIBCH are known to be pathogenic (PMID: 17160907, 26163321). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in an individual with HIBCH deficiency (PMID: 30111474).
Pediatric Department, Xiangya Hospital, Central South University	RCV001378527	SCV002761221	uncertain significance	Beta-hydroxyisobutyryl-CoA deacylase deficiency		criteria provided, single submitter	clinical testing	This variant was observed in compound heterozygosity with variant (c.958A>G)