ClinVar Miner

Submissions for variant NM_005327.7(HADH):c.261+1G>A

dbSNP: rs1398546361
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Mendelics RCV000987461 SCV001136756 pathogenic Deficiency of 3-hydroxyacyl-CoA dehydrogenase 2019-05-28 criteria provided, single submitter clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV001766803 SCV001999895 likely pathogenic Hyperinsulinemic hypoglycemia, familial, 4 2021-11-02 criteria provided, single submitter curation The c.261+1G>A variant in HADH has been reported in 1 individual with familial hyperinsulinemic hypoglycemia (PMID: 21347589) and has been identified in in 0.0009% (1/113718) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1398546361). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID#: 802082) and has been interpreted as likely pathogenic by Mendelics. In vitro functional studies provide some evidence that the c.261+1G>A variant may slightly impact protein function (PMID: 21347589). However, these types of assays may not accurately represent biological function. This variant is located in the 3' splice region. Computational tools predict a splicing impact, though this information is not predictive enough to determine pathogenicity. Loss of function of the HADH gene is strongly associated to autosomal recessive familial hyperinsulinemic hypoglycemia. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive familial hyperinsulinemic hypoglycemia. ACMG/AMP Criteria applied: PVS1_moderate, PM3_supporting, PM2_supporting, PS3_moderate (Richards 2015).
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic RCV003221307 SCV003915660 likely pathogenic Hyperinsulinemic hypoglycemia criteria provided, single submitter research Potent mutations in HADH gene are associated with congenital hyperinsulinism, which leads to recurrent hypoglycemia. The condition is exacerbated by stress, fasting or excessive dietary protein. May respond well to diazoxide. However, the role of this particular variant rs1398546361 in congenital hyperinsulinism is yet to be ascertained.

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