ClinVar Miner

Submissions for variant NM_000182.5(HADHA):c.1195C>T (p.Arg399Ter) (rs1243779049)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000523677 SCV000617631 pathogenic not provided 2017-08-29 criteria provided, single submitter clinical testing The R399X variant in the HADHA gene has been has been reported previously in mitochondrial trifunctional protein deficiency, in an affected individual who was compound heterozygous for the R399X variant and another pathogenic variant (Boutron et al., 2011). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R399X variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret R399X as a pathogenic variant.
Counsyl RCV000667154 SCV000791561 likely pathogenic Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency 2017-05-12 criteria provided, single submitter clinical testing
Genomic Research Center,Shahid Beheshti University of Medical Sciences RCV001169966 SCV001251679 pathogenic Mitochondrial trifunctional protein deficiency 2020-05-03 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000667154 SCV001337807 pathogenic Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency 2020-01-13 criteria provided, single submitter clinical testing Variant summary: HADHA c.1195C>T (p.Arg399X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251486 control chromosomes. c.1195C>T has been reported in the literature in at-least one individual affected with Long Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency who displayed MTP (Mitochondrial Trifunctional Protein) deficiency with a late infantile hepatic phenotype (Boutron_2011). These data support the notion that this variant is very likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported although haploinsufficiency has been reported as a major pathomechanism in MTP deficiency (Boutron_2011). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.