ClinVar Miner

Submissions for variant NM_000182.5(HADHA):c.2225_2228dup (p.Phe744fs)

dbSNP: rs868816467
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002271533 SCV000695946 likely pathogenic Mitochondrial trifunctional protein deficiency 2022-06-09 criteria provided, single submitter clinical testing Variant summary: HADHA c.2225_2228dupAACA (p.Phe744ThrfsX10) 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 4e-06 in 251478 control chromosomes. c.2225_2228dupAACA has been reported in the literature in individuals affected with Mitochondrial Trifunctional Protein Deficiency. These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV001860122 SCV002279368 pathogenic Mitochondrial trifunctional protein deficiency; Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency 2024-01-18 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Phe744Thrfs*10) in the HADHA gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 20 amino acid(s) of the HADHA protein. This variant is present in population databases (no rsID available, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with long-chain 3-hydroxyacyl-CoA dehydrogenase or mitochondrial trifunctional protein deficiency (PMID: 12237653, 21549624). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as AAAC insert at 2228. ClinVar contains an entry for this variant (Variation ID: 495727). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000590233 SCV004191778 pathogenic Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency 2023-05-27 criteria provided, single submitter clinical testing
Natera, Inc. RCV000590233 SCV002076486 likely pathogenic Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency 2020-11-09 no assertion criteria provided clinical testing

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