rs137852771

Variant names:

• chr2-26194581-G-A
• rs137852771
• NM_000182.5:c.1678C>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.1678C>T​(p.Arg560*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000227 in 1,453,704 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: 31)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: HADHA NM_000182.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: -0.126

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]

GAREM2 (HGNC:27172): (GRB2 associated regulator of MAPK1 subtype 2)

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 2-26194581-G-A is Pathogenic according to our data. Variant chr2-26194581-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 8732.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
HADHA	NM_000182.5	c.1678C>T	p.Arg560*	stop_gained	Exon 16 of 20	ENST00000380649.8	NP_000173.2
GAREM2	XM_011532567.4	c.1683+7266G>A		intron_variant	Intron 6 of 6		XP_011530869.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HADHA	ENST00000380649.8	c.1678C>T	p.Arg560*	stop_gained	Exon 16 of 20	1	NM_000182.5	ENSP00000370023.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 251462 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135904

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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: 0.0000352

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000227 AC: 33 AN: 1453704 Hom.: 0 Cov.: 29 AF XY: 0.0000193 AC XY: 14 AN XY: 723774

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000290

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

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:3

Oct 01, 2021

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PM2, PP5 -

Mar 14, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 29, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency;CN376812:Mitochondrial trifunctional protein deficiency 1 Pathogenic:1

Mar 22, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mitochondrial trifunctional protein deficiency 1 Pathogenic:1

Sep 01, 1996

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mitochondrial trifunctional protein deficiency Pathogenic:1

Jan 14, 2019

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: HADHA c.1678C>T (p.Arg560X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 2e-05 in 246244 control chromosomes (gnomAD). c.1678C>T has been reported in the literature in homozygote and compound heterozygote individuals affected with Long Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency (Boutron_2011, Boese_2016). The homozygote patient was found at a have a tritiated-palmitate levels of 13% and 3H-Pal/3H-Myr: normalized ratio between [9,10-3H]-palmitate and [9,10-3H]-myristate detritiation (both results expressed as percentages of the controls mean) of 0.6. This ratio is >0.85 in controls and other long chain fatty acid oxidation defects. 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. -

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

Feb 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg560*) 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 present in population databases (rs137852771, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with mitochondrial trifunctional protein deficiency (PMID: 8865274, 27491397). ClinVar contains an entry for this variant (Variation ID: 8732). 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	0.39	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.039
FATHMM_MKL	Benign	0.36	N
Vest4		0.96
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs137852771; hg19: chr2-26417450;