ClinVar Miner

Submissions for variant NM_014362.4(HIBCH):c.809+1G>A (rs143746450)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000480908 SCV000573943 pathogenic not provided 2017-03-03 criteria provided, single submitter clinical testing The c.809+1G>A variant in the HIBCH gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This splice site variant destroys the canonical splice donor site in intron 10. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.809+1G>A variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.809+1G>A as a pathogenic variant.
Laboratory for Molecular Medicine, Partners HealthCare 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,; 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 2018-01-02 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 10 of the HIBCH gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs143746450, ExAC 0.005%). This variant has not been reported in the literature in individuals with HIBCH-related disease. ClinVar contains an entry for this variant (Variation ID: 424160). 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). 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.

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