Submissions for variant NM_000182.5(HADHA):c.914T>C (p.Ile305Thr)

gnomAD frequency: 0.00001  dbSNP: rs137852774

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000520333	SCV000621873	likely pathogenic	not provided	2017-10-20	criteria provided, single submitter	clinical testing	The I305T variant in the HADHA gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The I305T variant is not observed in the homozygous state or at a significant frequency in large population cohorts (Lek et al., 2016). The I305T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. A missense variant in the same residue (I305N; I269N by alternate nomenclature) has been reported in the compound heterozygous state with another HADHA gene variant in an individual with recurrent episodes of muscle weakness and myoglobinuria, and reduced 3-hydroxyacyl-CoA activity activity in fibroblasts, supporting the functional importance of this region of the protein (Ibdah et al., 1998). We interpret I305T as a likely pathogenic variant.
Counsyl	RCV000674233	SCV000799535	uncertain significance	Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency	2018-04-24	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001853697	SCV002114412	likely pathogenic	Mitochondrial trifunctional protein deficiency; Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency	2023-08-30	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 305 of the HADHA protein (p.Ile305Thr). This variant is present in population databases (no rsID available, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with HADHA-related conditions. ClinVar contains an entry for this variant (Variation ID: 453019). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt HADHA protein function. This variant disrupts the p.Ile305 amino acid residue in HADHA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9739053, 21549624, 26109258). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003403243	SCV004122667	uncertain significance	not specified	2023-10-10	criteria provided, single submitter	clinical testing	Variant summary: HADHA c.914T>C (p.Ile305Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251006 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.914T>C in individuals affected with Long Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. Although, another variant in the same residue has been reported (I305N), the evidence for this variant is limited at this time to allow any conclusions. Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.