Submissions for variant NM_005327.7(HADH):c.374_375insTTCA (p.Lys125fs)

dbSNP: rs766656997

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000498051	SCV000589727	pathogenic	not provided	2017-05-26	criteria provided, single submitter	clinical testing	The c.374_375insTTCA pathogenic variant in the HADH gene is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant causes a frameshift starting with codon Lysine 125, changes this amino acid to a Asparagine residue and creates a premature Stop codon at position 17 of the new reading frame, denoted p.Lys125AsnfsX17. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Although this variant has not been previously reported to our knowledge, it is interpreted to be a pathogenic variant.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001764478	SCV001999896	uncertain significance	Hyperinsulinemic hypoglycemia, familial, 4	2021-11-02	criteria provided, single submitter	curation	The p.Lys125fs variant in HADH has not been previously reported in the literature in individuals with familial hyperinsulinemic hypoglycemia, but has been identified in 0.005% (1/18394) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs766656997). 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#: 432053) and has been interpreted as pathogenic by GeneDx. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 125 and leads to a premature termination codon 17 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the HADH gene is strongly associated to familial hyperinsulinemic hypoglycemia. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2_supporting, PVS1_strong (Richards 2015).
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV003222004	SCV003915734	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 rs766656997 in congenital hyperinsulinism is yet to be ascertained.