rs121913133

chr2-26279244-G-Achr2-26279244-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000183.3(HADHB):c.740G>A(p.Arg247His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000011 in 1,460,910 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R247C) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: HADHB NM_000183.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.53

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 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-26279243-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 2635256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.97
• PP5: Variant 2-26279244-G-A is Pathogenic according to our data. Variant chr2-26279244-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 14846.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.740G>A	p.Arg247His	missense_variant	9/16	ENST00000317799.10
HADHB	NM_001281512.2	c.695G>A	p.Arg232His	missense_variant	8/15
HADHB	NM_001281513.2	c.674G>A	p.Arg225His	missense_variant	10/17
HADHB	XM_011532803.2	c.740G>A	p.Arg247His	missense_variant	9/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HADHB	ENST00000317799.10	c.740G>A	p.Arg247His	missense_variant	9/16	1	NM_000183.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251412 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135878

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000110 AC: 16 AN: 1460910 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 726856

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mitochondrial trifunctional protein deficiency Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 09, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 22, 2023	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 247 of the HADHB protein (p.Arg247His). This variant is present in population databases (rs121913133, gnomAD 0.003%). This missense change has been observed in individuals with mitochondrial trifunctional protein deficiency (PMID: 8651282, 12754706). ClinVar contains an entry for this variant (Variation ID: 14846). 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. This variant disrupts the p.Arg247 amino acid residue in HADHB. Other variant(s) that disrupt this residue have been observed in individuals with HADHB-related conditions (PMID: 19699128), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Mitochondrial trifunctional protein deficiency 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 1996

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 09, 2017

The R247H variant was previously reported in three separate individuals with biochemical and clinicalfindings of MTP deficiency. All of these individuals were found to be heterozygous for another variantin the HADHB gene (Ushikubo et al., 1996; Spiekerkoetter et al., 2003). R247H was not observedwith any significant frequency in approximately 6500 individuals of European and African Americanancestry in the NHLBI Exome Sequencing Project. The R247H variant is a conservative amino acidsubstitution, which is not likely to impact secondary protein structure as these residues share similarproperties. This substitution occurs at a position that is conserved across species. In silico analysispredicts this variant is probably damaging to the protein structure/function. A missense variant in thesame residue (R247C) has been reported in the Human Gene Mutation Database in association withMTP deficiency (Stenson et al., 2014), supporting the functional importance of this region of theprotein. In summary, we interpret the R247H variant as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.41
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.67	D;D;.
Eigen	Uncertain	0.58
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Uncertain	0.69	D
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-4.7	D;D;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.045	D;D;D
Polyphen		0.13	B;B;.
Vest4		0.77
MutPred		0.91		.;Loss of helix (P = 0.0072);.;
MVP		0.98
MPC		0.21
ClinPred		0.96	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.85
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs121913133; hg19: chr2-26502112;