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

dbSNP: rs779113356

Total submissions: 5

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	2023-12-30	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. Loss-of-function variants in HADHA are known to be pathogenic (PMID: 7738175, 21103935, 21549624, 22459206). This variant is present in population databases (rs779113356, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency or deficiency of mitochondrial trifunctional protein (PMID: 10352164, 21549624). This variant is also known as Leu620Ter. ClinVar contains an entry for this variant (Variation ID: 188712). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000169001	SCV004191763	pathogenic	Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency	2023-08-21	criteria provided, single submitter	clinical testing