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

dbSNP: rs868816467

Total submissions: 4

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.
Labcorp Genetics (formerly Invitae), Labcorp	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	2024-03-08	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