2-26285546-T-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000183.3(HADHB):c.1364T>G(p.Val455Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,776 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: HADHB NM_000183.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.91

Genes affected

HADHB (HGNC:4803): (hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit beta) This gene encodes the beta subunit of the mitochondrial trifunctional protein, which catalyzes the last three steps of mitochondrial beta-oxidation of long chain fatty acids. The mitochondrial membrane-bound heterocomplex is composed of four alpha and four beta subunits, with the beta subunit catalyzing the 3-ketoacyl-CoA thiolase activity. The encoded protein can also bind RNA and decreases the stability of some mRNAs. The genes of the alpha and beta subunits of the mitochondrial trifunctional protein are located adjacent to each other in the human genome in a head-to-head orientation. Mutations in this gene result in trifunctional protein deficiency. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2013]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.945
• PP5: Variant 2-26285546-T-G is Pathogenic according to our data. Variant chr2-26285546-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 14849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HADHB	NM_000183.3	c.1364T>G	p.Val455Gly	missense_variant	15/16	ENST00000317799.10
HADHB	NM_001281512.2	c.1319T>G	p.Val440Gly	missense_variant	14/15
HADHB	NM_001281513.2	c.1298T>G	p.Val433Gly	missense_variant	16/17
HADHB	XM_011532803.2	c.1364T>G	p.Val455Gly	missense_variant	15/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HADHB	ENST00000317799.10	c.1364T>G	p.Val455Gly	missense_variant	15/16	1	NM_000183.3	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251356 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135860

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461776 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727192

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mitochondrial trifunctional protein deficiency Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 09, 2020	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jun 17, 2023	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). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2009	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 12, 2022

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) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.43
Cadd	Pathogenic	29
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.66	D;D;D;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.94	D;D;D;D
MetaSVM	Pathogenic	0.87	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-6.3	D;D;D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		0.92	P;P;D;.
Vest4		0.66
MutPred		0.84		.;Gain of helix (P = 0.0034);.;.;
MVP		1.0
MPC		0.61
ClinPred		0.98	D
GERP RS		5.7
Varity_R		0.95
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs267606859; hg19: chr2-26508414;