Submissions for variant NM_005327.7(HADH):c.662G>A (p.Arg221His)

gnomAD frequency: 0.00358  dbSNP: rs76476980

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Personalized Diabetes Medicine Program, University of Maryland School of Medicine	RCV000445511	SCV000537024	uncertain significance	Monogenic diabetes	2018-01-12	criteria provided, single submitter	research	ACMG criteria: PP3 (10 predictors), BS2 (27 cases and 24 controls in type2diabetesgenetics.org)=VUS NOTE: GeneDx also calls VUS
GeneDx	RCV000521350	SCV000617017	uncertain significance	not provided	2015-04-01	criteria provided, single submitter	clinical testing	The R221H variant in the HADH gene has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The NHLBI ESP Exome Sequencing Project reports R221H was observed in 42/4406 alleles (0.95%) from individuals of African American background, indicating it may be a rare variant in this population. The R221H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. A missense pathogenic variant in a nearby residues (Y226H) has been reported in the Human Gene Mutation Database in association with hyperinsulinemic hypoglycemia (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret R221H as a variant of unknown significance.
Fulgent Genetics, Fulgent Genetics	RCV000764524	SCV000895607	uncertain significance	Deficiency of 3-hydroxyacyl-CoA dehydrogenase; Hyperinsulinemic hypoglycemia, familial, 4	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001084606	SCV001013401	benign	Deficiency of 3-hydroxyacyl-CoA dehydrogenase	2024-01-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001084606	SCV001306522	benign	Deficiency of 3-hydroxyacyl-CoA dehydrogenase	2017-06-26	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV001145824	SCV001306523	benign	Hyperinsulinemic hypoglycemia, familial, 4	2017-06-26	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Genetic Services Laboratory, University of Chicago	RCV001821213	SCV002071094	benign	not specified	2019-03-07	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000521350	SCV002821265	benign	not provided	2022-10-01	criteria provided, single submitter	clinical testing	HADH: BS1, BS2
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV001145824	SCV003915741	likely pathogenic	Hyperinsulinemic hypoglycemia, familial, 4	2024-02-10	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 rs76476980 in hyperinsulinemic hypoglycemia is yet to be ascertained. This variant is a potent moderate impact, deleterious variant with a CADD score of 31. This gene is found to be frequently associated with Hyperinsulinemic hypoglycemia as per recent evidence as well, with sufficient scientific evidence to support the reported classification. Loss of function mutations in HADH can potentially cause protein-induced hyperinsulinemic hypoglycemia