Submissions for variant NM_000183.3(HADHB):c.181C>T (p.Arg61Cys)

gnomAD frequency: 0.00001  dbSNP: rs780351691

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000518877	SCV000617634	likely pathogenic	not provided	2020-06-26	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 28112527, 12754706)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001197680	SCV004122668	pathogenic	Mitochondrial trifunctional protein deficiency	2023-10-10	criteria provided, single submitter	clinical testing	Variant summary: HADHB c.181C>T (p.Arg61Cys aka. R28C) results in a non-conservative amino acid change located in the Thiolase, N-terminal domain (IPR020616) 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 1.6e-05 in 251490 control chromosomes (gnomAD). The variant c.181C>T has been reported in the literature in homozygous and compound heterozygous individuals affected with Mitochondrial Trifunctional Protein Deficiency (e.g. Spiekerkoetter_2003, Spiekerkoetter_2004, Schwantje_2022). These data indicate that the variant is likely to be associated with disease. Publication also reported reports experimental evidence evaluating an impact on protein function and demonstrated decreased enzyme activities in patient derived cells (Spiekerkoetter_2003, Spiekerkoetter_2004, Schwantje_2022), and decreased expression and abolished protein interaction with HADHA in an in vitro expression system (Naiki_2014). The following publications have been ascertained in the context of this evaluation (PMID: 24664533, 12754706, 14694500, 35383965). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as likely pathogenic, while the other submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV004568664	SCV004191806	likely pathogenic	Mitochondrial trifunctional protein deficiency 1	2024-03-26	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001197680	SCV004292064	pathogenic	Mitochondrial trifunctional protein deficiency	2023-12-01	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 61 of the HADHB protein (p.Arg61Cys). This variant is present in population databases (rs780351691, gnomAD 0.006%). This missense change has been observed in individual(s) with mitochondrial trifunctional protein deficiency (PMID: 12754706). This variant is also known as R28C. ClinVar contains an entry for this variant (Variation ID: 449456). 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.Arg61 amino acid residue in HADHB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8651282, 12754706, 16423905). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001197680	SCV001368459	uncertain significance	Mitochondrial trifunctional protein deficiency	2020-03-07	flagged submission	clinical testing	This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PM2,PP3.