ClinVar Miner

Submissions for variant NM_000182.5(HADHA):c.1793_1794del (p.His598fs) (rs769580842)

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Total submissions: 4
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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 RCV000169337 SCV000917471 pathogenic Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency 2018-10-22 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. The variant allele was found at a frequency of 3.2e-05 in 277226 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). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV001041924 SCV001205577 pathogenic Mitochondrial trifunctional protein deficiency; Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency 2020-08-27 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. This variant is present in population databases (rs769580842, ExAC 0.01%). This variant has been observed in an individual affected with mitochondrial trifunctional protein deficiency (PMID: 11855930). ClinVar contains an entry for this variant (Variation ID: 188962). Loss-of-function variants in HADHA are known to be pathogenic (PMID: 7738175, 21103935, 21549624, 22459206). For these reasons, this variant has been classified as Pathogenic.
Natera, Inc. RCV000169337 SCV001458396 pathogenic Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency 2020-09-16 no assertion criteria provided clinical testing

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