Submissions for variant NM_000182.5(HADHA):c.1793_1794del (p.His598fs)

gnomAD frequency: 0.00003  dbSNP: rs769580842

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169337	SCV000220683	likely pathogenic	Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency	2014-09-10	criteria provided, single submitter	literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001778769	SCV000917471	pathogenic	Mitochondrial trifunctional protein deficiency	2021-10-17	criteria provided, single submitter	clinical testing	Variant summary: HADHA c.1793_1794delAT (p.His598ArgfsX33) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 2.8e-05 in 251486 control chromosomes (gnomAD). c.1793_1794delAT has been reported in the literature in individuals affected with Mitochondrial trifunctional protein deficiency (MTFP); in a homozygous patient with maternal uniparental disomy for chromosome 2 (Hintz 2002, Spiekerkoetter 2002) and in two other patients, where one of them was a confirmed homozygote (Lee 2003, Kang 2018). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on enzyme activity in cultured fibroblasts which revealed marked deficiencies in both LCHAD and LKAT activities, consistent with complete TFP deficiency. Acylcarnitine analysis of a blood spot from the original newborn screening card was also consistent with the established diagnosis (Hintz 2002). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001041924	SCV001205577	pathogenic	Mitochondrial trifunctional protein deficiency; Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency	2023-12-01	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.His598Argfs*33) in the HADHA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HADHA are known to be pathogenic (PMID: 7738175, 21103935, 21549624, 22459206). This variant is present in population databases (rs769580842, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with mitochondrial trifunctional protein deficiency (PMID: 11855930). This variant is also known as 1793-94delAT, R593ter. ClinVar contains an entry for this variant (Variation ID: 188962). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV003153460	SCV003842532	pathogenic	not provided	2020-04-09	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 11855930, 29519241, 31980526, 12442268, 12971428, 31589614, 32778825)
Baylor Genetics	RCV000169337	SCV004191774	pathogenic	Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency	2024-03-26	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV003153460	SCV004226540	likely pathogenic	not provided	2022-02-01	criteria provided, single submitter	clinical testing	PM2, PS3_supporting, PVS1
New York Genome Center	RCV004554742	SCV005044146	pathogenic	Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency; Mitochondrial trifunctional protein deficiency 1	2022-09-23	criteria provided, single submitter	clinical testing	The homozygous c.1793_1794del, p.(His598ArgfsTer33) variant identified in the HADHA gene is a deletion of two nucleotides in exon# 17 of this 20-exon gene which alters the wild-type translational reading frame and is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. This variant is found with low frequency in population databases gnomADv2.1.1, gnomADv3.1.2, TOPMed Freeze 8 (21 out of 590,312 heterozygous alleles, no homozygotes) suggesting it is not a common benign variant in the populations represented in those databases. This variant is reported as Pathogenic / Likely Pathogenic in ClinVar (Variation ID: 188962) and has been reported as homozygous in at least two unrelated infants affected with HADHA-related disorders [PMID: 29519241, 11855930]; a newborn with severe cardiomyopathy at first day of life who died of lactic acidosis at 4 days old [PMID: 29519241], and in another newborn with mitochondrial TFP deficiency [PMID: 11855930]. Given its deleterious nature, low frequency in population databases, and prior observation as homozygous in apparently unrelated affected neonates in the literature, the homozygous c.1793_1794del, p.(His598ArgfsTer33) variant identified in the HADHA gene is reported here as Pathogenic.
Natera, Inc.	RCV000169337	SCV001458396	pathogenic	Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency	2020-09-16	no assertion criteria provided	clinical testing