rs137852775

chr2-26214490-G-Achr2-26214490-G-Cchr2-26214490-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000182.5(HADHA):c.871C>T(p.Arg291Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000826 in 1,452,922 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000083 (0 hom.)
• Consequence: HADHA NM_000182.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 4.31

Genes affected

HADHA (HGNC:4801): (hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit alpha) This gene encodes the alpha 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 alpha subunit catalyzing the 3-hydroxyacyl-CoA dehydrogenase and enoyl-CoA hydratase activities. Mutations in this gene result in trifunctional protein deficiency or LCHAD deficiency. 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. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-26214490-G-A is Pathogenic according to our data. Variant chr2-26214490-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 8737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HADHA	NM_000182.5	c.871C>T	p.Arg291Ter	stop_gained	9/20	ENST00000380649.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HADHA	ENST00000380649.8	c.871C>T	p.Arg291Ter	stop_gained	9/20	1	NM_000182.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000826 AC: 12 AN: 1452922 Hom.: 0 Cov.: 29 AF XY: 0.00000968 AC XY: 7 AN XY: 723366

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000814

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 17, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 27, 2020	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Apr 08, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 26, 2017	Variant summary: The HADHA c.871C>T (p.Arg291X) variant results in a premature termination codon, predicted to cause a truncated or absent HADHA protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant is absent in 121364 control chromosomes. Multiple publications have cited the variant in affected individuals, along with functional studies indicating no detectable protein levels were observed (Ibdah_1998). In addition, a reputable database classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 14, 2023

The c.871C>T (p.R291*) alteration, located in exon 9 (coding exon 9) of the HADHA gene, consists of a C to T substitution at nucleotide position 871. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 291. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been detected in conjunction with a HADHA variant in two individuals a diagnosis of LCHAD deficiency and in one individual with clinical features of MTP; however, the phase of the two variants was not specified (Ibdah, 1998; Waisbren, 2013; Squires, 2023). Based on the available evidence, this alteration is classified as pathogenic. -

Mitochondrial trifunctional protein deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 15, 1998

- -

Mitochondrial trifunctional protein deficiency;C3711645:Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 12, 2024

This sequence change creates a premature translational stop signal (p.Arg291*) in the HADHA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HADHA are known to be pathogenic (PMID: 7738175, 21103935, 21549624, 22459206). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with trifunctional protein deficiency (PMID: 9739053). ClinVar contains an entry for this variant (Variation ID: 8737). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
Cadd	Pathogenic	37
Dann	Uncertain	1.0
Eigen	Pathogenic	0.80
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.91	D
MutationTaster	Benign	1.0	A;A
Vest4		0.92
GERP RS		3.4

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs137852775; hg19: chr2-26437359; COSMIC: COSV66106265; COSMIC: COSV66106265;