Submissions for variant NM_014362.4(HIBCH):c.809+1G>A

dbSNP: rs143746450

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000480908	SCV000573943	likely pathogenic	not provided	2021-05-18	criteria provided, single submitter	clinical testing	Reported as a single heterozygous variant in a newborn undergoing exome sequencing through the BabySeq Project (Ceyhan-Birsoy et al., 2019); Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 30609409)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000607054	SCV000712798	likely pathogenic	Beta-hydroxyisobutyryl-CoA deacylase deficiency	2017-01-31	criteria provided, single submitter	clinical testing	The c.809+1G>A (NM_014362.3 c.809+1G>A) variant in HIBCH has not been reported i n individuals with 3-Hydroxyisobutyrl-CoA hydrolase deficiency (HIBCH deficiency ) and has been identified in 0.005% (3/58,196) of European chromosomes by the Ex ome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs143746 450). Although this variant has been seen in the general population, its frequen cy is low enough to be consistent with a recessive carrier frequency. This varia nt occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein . Biallelic loss of function of the HIBCH gene has been associated with 3-Hydrox yisobutyrl-CoA hydrolase deficiency. In summary, although additional studies are required to fully establish a null effect on the protein, this variant meets cr iteria to be classified as likely pathogenic for HIBCH deficiency in an autosoma l recessive manner based upon its predicted functional impact.
Invitae	RCV000607054	SCV000818747	likely pathogenic	Beta-hydroxyisobutyryl-CoA deacylase deficiency	2023-03-23	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 424160). This variant has not been reported in the literature in individuals affected with HIBCH-related conditions. This variant is present in population databases (rs143746450, gnomAD 0.006%). This sequence change affects a donor splice site in intron 10 of the HIBCH 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 HIBCH are known to be pathogenic (PMID: 17160907, 26163321).
Genetic Services Laboratory, University of Chicago	RCV000480908	SCV002064475	likely pathogenic	not provided	2018-05-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000607054	SCV004222851	likely pathogenic	Beta-hydroxyisobutyryl-CoA deacylase deficiency	2023-11-17	criteria provided, single submitter	clinical testing	Variant summary: HIBCH c.809+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. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.6e-05 in 249446 control chromosomes. To our knowledge, no occurrence of c.809+1G>A in individuals affected with Beta-Hydroxyisobutyryl Deacylase Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.