Submissions for variant NM_000183.3(HADHB):c.881C>G (p.Pro294Arg)

dbSNP: rs1558357879

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000779320	SCV000915903	likely pathogenic	HADHA-related disorder	2018-11-05	criteria provided, single submitter	clinical testing	The HADHB c.881C>G (p.Pro294Arg) variant is a missense variant that has been reported in a compound heterozygous state in two unrelated individuals with trifunctional protein deficiency (Spiekerkoetter et al. 2003, 2004). Deficient LCHAD and LKAT enzyme activity was observed in fibroblasts from both individuals. Another missense change at the same position was also reported in affected individuals. The p.Pro294Arg variant, which was previously known as p.Pro261Arg, was absent from 100 control individuals and is not reported in the 1000 Genomes Project, Exome Sequencing Project, Exome Aggregation Consortium, or Genome Aggregation Database despite its location in a region of good sequencing coverage. It is therefore presumed to be rare. Based on the collective evidence, the p.Pro294Arg variant is classified as likely pathogenic for HADHA-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Baylor Genetics	RCV003465712	SCV004191828	likely pathogenic	Mitochondrial trifunctional protein deficiency	2023-06-29	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003465712	SCV004292068	pathogenic	Mitochondrial trifunctional protein deficiency	2023-12-06	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 294 of the HADHB protein (p.Pro294Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Mitochondrial trifunctional protein deficiency (PMID: 12754706). This variant is also known as P261R. ClinVar contains an entry for this variant (Variation ID: 632355). 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 with a positive predictive value of 80%. This variant disrupts the p.Pro294 amino acid residue in HADHB. Other variant(s) that disrupt this residue have been observed in individuals with HADHB-related conditions (PMID: 12754706), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.