Submissions for variant NM_000183.3(HADHB):c.1364T>G (p.Val455Gly)

dbSNP: rs267606859

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000015974	SCV001372238	pathogenic	Mitochondrial trifunctional protein deficiency	2020-06-09	criteria provided, single submitter	clinical testing	Variant summary: HADHB c.1364T>G (p.Val455Gly) results in a non-conservative amino acid change located in the Thiolase, C-terminal domain (IPR020617) of 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 251356 control chromosomes. c.1364T>G has been reported in the literature in individuals affected with Mitochondrial Trifunctional Protein Deficiency and has been subsequently cited by others (example, Purevsuren_2009, Park_2009, Bo_2017, Boutron_2011, Bo_2016). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Purevsuren_2009). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000015974	SCV001581368	pathogenic	Mitochondrial trifunctional protein deficiency	2023-06-17	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects HADHB function (PMID: 19699128, 26109258). 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 not expected to disrupt HADHB protein function. ClinVar contains an entry for this variant (Variation ID: 14849). This missense change has been observed in individual(s) with mitochondrial trifunctional protein deficiency (PMID: 19699128, 19880769; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs267606859, gnomAD 0.006%). This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 455 of the HADHB protein (p.Val455Gly).
GeneDx	RCV003125832	SCV003803492	pathogenic	not provided	2022-08-12	criteria provided, single submitter	clinical testing	Published functional studies found this variant is associated with significantly reduced long-chain 3-ketoacyl-CoA thiolase activity (Purevsuren J et al., 2009); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19880769, 21549624, 19699128, 27014569, 28515471, 32509533)
OMIM	RCV000015974	SCV000036241	pathogenic	Mitochondrial trifunctional protein deficiency	2009-12-01	no assertion criteria provided	literature only