ClinVar Miner

Submissions for variant NM_000182.5(HADHA):c.1967del (p.Ile655_Leu656insTer) (rs779113356)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169001 SCV000220140 likely pathogenic Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency 2014-03-04 criteria provided, single submitter literature only
GeneDx RCV000255407 SCV000322387 pathogenic not provided 2016-08-11 criteria provided, single submitter clinical testing The c.1967delT has previously been reported as c.1964delT in association with LCHAD deficiency (Ibdah et al., 1999). This variant results in the normal codon, Leucine 656, being replaced by a Stop codon and is denoted p.L656X. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Therefore we interpret c.1967delT to be a pathogenic variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169001 SCV000695944 pathogenic Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency 2017-05-22 criteria provided, single submitter clinical testing Variant summary: The HADHA c.1967delT (p.Leu656X) variant results in a premature termination codon, predicted to cause a truncated or absent HADHA protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 1/121390 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic HADHA variant (0.0019365). This variant has been reported in multiple patients as compound heterozygotes (Ibdah_!999 and Boutron_2011). One of patients showed 26% of residual LCHAD activity relative to the controls mean in fibroblasts and 2% of residual LKAT activity relative to the controls mean (Boutron_2011). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic/likely pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV001239627 SCV001412513 pathogenic Mitochondrial trifunctional protein deficiency; Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency 2019-10-21 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Leu656*) in the HADHA gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs779113356, ExAC 0.001%). This variant has been observed in individuals affected with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency or deficiency of mitochondrial trifunctional protein (PMID: 10352164, 21549624). This variant is also known as Leu620Ter in the literature. ClinVar contains an entry for this variant (Variation ID: 188712). 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.

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