chr2-26285546-T-G

Variant names:

• chr2-26285546-T-G
• rs267606859
• NM_000183.3:c.1364T>G

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM2 PP2 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:5
• Conservation: PhyloP100: 7.91
• Publications: 7 publications found

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]

HADHB Gene-Disease associations (from GenCC):

• mitochondrial trifunctional protein deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet, ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000183.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 25 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 0.64924 (below the threshold of 3.09). Trascript score misZ: 0.82597 (below the threshold of 3.09). GenCC associations: The gene is linked to mitochondrial trifunctional protein deficiency.
• 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 CliVar as Pathogenic. Clinvar id is 14849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26285546-T-G is described in CliVar as Pathogenic. Clinvar id is 14849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26285546-T-G is described in CliVar as Pathogenic. Clinvar id is 14849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26285546-T-G is described in CliVar as Pathogenic. Clinvar id is 14849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26285546-T-G is described in CliVar as Pathogenic. Clinvar id is 14849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26285546-T-G is described in CliVar as Pathogenic. Clinvar id is 14849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26285546-T-G is described in CliVar as Pathogenic. Clinvar id is 14849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26285546-T-G is described in CliVar as Pathogenic. Clinvar id is 14849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26285546-T-G is described in CliVar as Pathogenic. Clinvar id is 14849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26285546-T-G is described in CliVar as Pathogenic. Clinvar id is 14849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26285546-T-G is described in CliVar as Pathogenic. Clinvar id is 14849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26285546-T-G is described in CliVar as Pathogenic. Clinvar id is 14849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26285546-T-G is described in CliVar as Pathogenic. Clinvar id is 14849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26285546-T-G is described in CliVar as Pathogenic. Clinvar id is 14849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26285546-T-G is described in CliVar as Pathogenic. Clinvar id is 14849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26285546-T-G is described in CliVar as Pathogenic. Clinvar id is 14849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26285546-T-G is described in CliVar as Pathogenic. Clinvar id is 14849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26285546-T-G is described in CliVar as Pathogenic. Clinvar id is 14849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26285546-T-G is described in CliVar as Pathogenic. Clinvar id is 14849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26285546-T-G is described in CliVar as Pathogenic. Clinvar id is 14849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26285546-T-G is described in CliVar as Pathogenic. Clinvar id is 14849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26285546-T-G is described in CliVar as Pathogenic. Clinvar id is 14849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26285546-T-G is described in CliVar as Pathogenic. Clinvar id is 14849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26285546-T-G is described in CliVar as Pathogenic. Clinvar id is 14849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26285546-T-G is described in CliVar as Pathogenic. Clinvar id is 14849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26285546-T-G is described in CliVar as Pathogenic. Clinvar id is 14849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26285546-T-G is described in CliVar as Pathogenic. Clinvar id is 14849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26285546-T-G is described in CliVar as Pathogenic. Clinvar id is 14849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26285546-T-G is described in CliVar as Pathogenic. Clinvar id is 14849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26285546-T-G is described in CliVar as Pathogenic. Clinvar id is 14849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26285546-T-G is described in CliVar as Pathogenic. Clinvar id is 14849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26285546-T-G is described in CliVar as Pathogenic. Clinvar id is 14849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26285546-T-G is described in CliVar as Pathogenic. Clinvar id is 14849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26285546-T-G is described in CliVar as Pathogenic. Clinvar id is 14849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26285546-T-G is described in CliVar as Pathogenic. Clinvar id is 14849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26285546-T-G is described in CliVar as Pathogenic. Clinvar id is 14849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26285546-T-G is described in CliVar as Pathogenic. Clinvar id is 14849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26285546-T-G is described in CliVar as Pathogenic. Clinvar id is 14849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26285546-T-G is described in CliVar as Pathogenic. Clinvar id is 14849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26285546-T-G is described in CliVar as Pathogenic. Clinvar id is 14849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26285546-T-G is described in CliVar as Pathogenic. Clinvar id is 14849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26285546-T-G is described in CliVar as Pathogenic. Clinvar id is 14849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26285546-T-G is described in CliVar as Pathogenic. Clinvar id is 14849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26285546-T-G is described in CliVar as Pathogenic. Clinvar id is 14849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26285546-T-G is described in CliVar as Pathogenic. Clinvar id is 14849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26285546-T-G is described in CliVar as Pathogenic. Clinvar id is 14849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26285546-T-G is described in CliVar as Pathogenic. Clinvar id is 14849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26285546-T-G is described in CliVar as Pathogenic. Clinvar id is 14849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26285546-T-G is described in CliVar as Pathogenic. Clinvar id is 14849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26285546-T-G is described in CliVar 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 rank	MANE	Protein	UniProt
HADHB	NM_000183.3	c.1364T>G	p.Val455Gly	missense_variant	Exon 15 of 16	ENST00000317799.10	NP_000174.1
HADHB	NM_001281512.2	c.1319T>G	p.Val440Gly	missense_variant	Exon 14 of 15		NP_001268441.1
HADHB	NM_001281513.2	c.1298T>G	p.Val433Gly	missense_variant	Exon 16 of 17		NP_001268442.1
HADHB	XM_011532803.2	c.1364T>G	p.Val455Gly	missense_variant	Exon 15 of 16		XP_011531105.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HADHB	ENST00000317799.10	c.1364T>G	p.Val455Gly	missense_variant	Exon 15 of 16	1	NM_000183.3	ENSP00000325136.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251356 AF XY: 0.00000736

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111930

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000360 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mitochondrial trifunctional protein deficiency Pathogenic:3

Dec 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jun 09, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Jun 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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). -

Mitochondrial trifunctional protein deficiency 2 Pathogenic:1

Jan 15, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Aug 12, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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) -

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
MutationAssessor	Benign	1.5	.;L;.;.
PhyloP100		7.9
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
Mutation Taster		=4/96	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs267606859; hg19: chr2-26508414;