Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000481427 | SCV000566916 | likely pathogenic | not provided | 2017-03-09 | criteria provided, single submitter | clinical testing | The R247H variant was previously reported in three separate individuals with biochemical and clinicalfindings of MTP deficiency. All of these individuals were found to be heterozygous for another variantin the HADHB gene (Ushikubo et al., 1996; Spiekerkoetter et al., 2003). R247H was not observedwith any significant frequency in approximately 6500 individuals of European and African Americanancestry in the NHLBI Exome Sequencing Project. The R247H variant is a conservative amino acidsubstitution, which is not likely to impact secondary protein structure as these residues share similarproperties. This substitution occurs at a position that is conserved across species. In silico analysispredicts this variant is probably damaging to the protein structure/function. A missense variant in thesame residue (R247C) has been reported in the Human Gene Mutation Database in association withMTP deficiency (Stenson et al., 2014), supporting the functional importance of this region of theprotein. In summary, we interpret the R247H variant as likely pathogenic. |
| Baylor Genetics | RCV003460481 | SCV004191821 | likely pathogenic | Mitochondrial trifunctional protein deficiency | 2023-09-09 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV003460481 | SCV004284847 | pathogenic | Mitochondrial trifunctional protein deficiency | 2023-09-22 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 247 of the HADHB protein (p.Arg247His). This variant is present in population databases (rs121913133, gnomAD 0.003%). This missense change has been observed in individuals with mitochondrial trifunctional protein deficiency (PMID: 8651282, 12754706). ClinVar contains an entry for this variant (Variation ID: 14846). 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 HADHB protein function. This variant disrupts the p.Arg247 amino acid residue in HADHB. Other variant(s) that disrupt this residue have been observed in individuals with HADHB-related conditions (PMID: 19699128), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. |
| OMIM | RCV003156216 | SCV000036238 | pathogenic | Mitochondrial trifunctional protein deficiency 2 | 1996-05-01 | no assertion criteria provided | literature only |