Submissions for variant NM_005327.7(HADH):c.643C>A (p.Pro215Thr)

gnomAD frequency: 0.00198  dbSNP: rs140413151

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Personalized Diabetes Medicine Program, University of Maryland School of Medicine	RCV000664101	SCV000787553	uncertain significance	Monogenic diabetes	2017-03-31	criteria provided, single submitter	research	ACMG Criteria:PP3 (11 predictors), BS2 (18 cases and 25 controls in type2diabetesgenetics.org for AD monogenic diabetes; two homozygotes in ExAC)
Fulgent Genetics, Fulgent Genetics	RCV000764523	SCV000895606	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	RCV001082981	SCV001014836	likely benign	Deficiency of 3-hydroxyacyl-CoA dehydrogenase	2025-01-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000872937	SCV001154224	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	HADH: BS2
Illumina Laboratory Services, Illumina	RCV001145823	SCV001306520	uncertain significance	Hyperinsulinemic hypoglycemia, familial, 4	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001082981	SCV001306521	uncertain significance	Deficiency of 3-hydroxyacyl-CoA dehydrogenase	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV000872937	SCV001779548	likely benign	not provided	2021-05-28	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32876354, 25007923)
Genetic Services Laboratory, University of Chicago	RCV001816664	SCV002071093	likely benign	not specified	2021-12-03	criteria provided, single submitter	clinical testing	This sequence change does not appear to have been previously described in individuals with HADH-related disorders. This sequence change has been described in the gnomAD database with a frequency of 0.014% (dbSNP rs140413151). The p.Pro215Thr change affects a highly conserved amino acid residue located in a domain of the HADH protein that is not known to be functional. The p.Pro215Thr substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to insufficient evidence and the lack of functional studies, the clinical significance of the p.Pro215Thr change remains unknown at this time.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV003222089	SCV003915740	uncertain risk allele	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 rs140413151 in congenital hyperinsulinism is yet to be ascertained.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000764523	SCV006053729	likely benign	Deficiency of 3-hydroxyacyl-CoA dehydrogenase; Hyperinsulinemic hypoglycemia, familial, 4	2022-02-08	criteria provided, single submitter	research
PreventionGenetics, part of Exact Sciences	RCV003953224	SCV004767200	likely benign	HADH-related disorder	2022-10-11	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).