ClinVar Miner

Submissions for variant NM_000182.5(HADHA):c.703C>T (p.Arg235Trp)

dbSNP: rs786204607
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169366 SCV000220741 likely pathogenic Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency 2014-09-26 criteria provided, single submitter literature only
GeneDx RCV000421144 SCV000521115 likely pathogenic not provided 2018-11-08 criteria provided, single submitter clinical testing The R235W variant in the HADHA gene has been reported previously in the homozygous state in three unrelated individuals with MTP deficiency (Scheuerman et al., 2009; Boutron et al., 2011). The R235W variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R235W 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, and in silico analysis predicts this variant is probably damaging to the protein structure/function. The R235W variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
CeGaT Center for Human Genetics Tuebingen RCV000421144 SCV001501263 likely pathogenic not provided 2020-07-01 criteria provided, single submitter clinical testing
Invitae RCV002515195 SCV003523966 pathogenic Mitochondrial trifunctional protein deficiency; Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency 2023-03-19 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 235 of the HADHA protein (p.Arg235Trp). For these reasons, this variant has been classified as Pathogenic. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on HADHA protein function. ClinVar contains an entry for this variant (Variation ID: 188987). This missense change has been observed in individual(s) with mitochondrial trifunctional protein deficiency (PMID: 19433283, 21549624, 34878152). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency).
Baylor Genetics RCV000169366 SCV004191750 pathogenic Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency 2023-10-14 criteria provided, single submitter clinical testing
Natera, Inc. RCV000169366 SCV001462517 likely pathogenic Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency 2020-09-16 no assertion criteria provided clinical testing
OMIM RCV003223391 SCV003840966 pathogenic Mitochondrial trifunctional protein deficiency 2023-03-27 no assertion criteria provided literature only

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