2-26195184-C-G

Position:

chr2-26195184-C-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 11P and 1B. PM2PP3PP5_Very_StrongBP4

The NM_000182.5(HADHA):c.1528G>C(p.Glu510Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00134 in 1,612,330 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.0010 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0014 ( 0 hom. )

Consequence

HADHA
NM_000182.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:27

Conservation

PhyloP100: 7.76

Variant links:

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]

HADHA links:

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

GAREM2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, M_CAP, MutationAssessor, phyloP100way_vertebrate, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

PP5

Variant 2-26195184-C-G is Pathogenic according to our data. Variant chr2-26195184-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 100085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26195184-C-G is described in Lovd as [Pathogenic]. Variant chr2-26195184-C-G is described in Lovd as [Likely_benign]. Variant chr2-26195184-C-G is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.11454907). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HADHA	NM_000182.5 linkuse as main transcript	c.1528G>C	p.Glu510Gln	missense_variant	15/20	ENST00000380649.8	NP_000173.2	P40939-1E9KL44
GAREM2	XM_011532567.4 linkuse as main transcript	c.1684-7049C>G		intron_variant			XP_011530869.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HADHA	ENST00000380649.8 linkuse as main transcript	c.1528G>C	p.Glu510Gln	missense_variant	15/20	1	NM_000182.5	ENSP00000370023.3		P40939-1

Frequencies

GnomAD3 genomes

AF:

0.00101

AC:

153

AN:

152014

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000459

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00273

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00162

Gnomad OTH

AF:

0.000959

GnomAD3 exomes

AF:

0.00123

AC:

309

AN:

251462

Hom.:

AF XY:

0.00113

AC XY:

153

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.000838

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00402

Gnomad NFE exome

AF:

0.00152

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.00138

AC:

2009

AN:

1460198

Hom.:

Cov.:

AF XY:

0.00130

AC XY:

946

AN XY:

726496

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.000827

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000104

Gnomad4 FIN exome

AF:

0.00464

Gnomad4 NFE exome

AF:

0.00148

Gnomad4 OTH exome

AF:

0.00109

GnomAD4 genome

AF:

0.00101

AC:

153

AN:

152132

Hom.:

Cov.:

AF XY:

0.00117

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.000459

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00273

Gnomad4 NFE

AF:

0.00162

Gnomad4 OTH

AF:

0.000949

Alfa

AF:

0.00132

Hom.:

Bravo

AF:

0.000706

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.00120

AC:

146

EpiCase

AF:

0.00131

EpiControl

AF:

0.00136

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:27

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency

Pathogenic:10

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 27, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 13, 2019	NM_000182.4(HADHA):c.1528G>C(E510Q, aka E474Q) is classified as pathogenic in the context of HADHA-related disorders. Sources cited for classification include the following: PMID 7811722, 15902556 and 8770876. Classification of NM_000182.4(HADHA):c.1528G>C(E510Q, aka E474Q) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 07, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 27, 2016	The p.Glu510Gln variant in HADHA has been reported in >25 individuals with Long- chain 3-hydroxyacyl-CoA dehydrogenase deficiency in the homozygous and compound heterozygous state (Ijlst 1994, Baskin 2010, Olpin 2005) and is the most common cause of LCHAD deficiency (Polinati 2015). This variant has been identified in 0 .168% (112/66738) of European chromosomes by the Exome Aggregation Consortium (E xAC, http://exac.broadinstitute.org; dbSNP rs137852769). Although this variant h as been seen in the general population, its frequency is low enough to be consis tent with a recessive carrier frequency. In vitro functional studies provide som e evidence that the p.Glu510Gln variant may impact protein function (Polinati 20 15). In summary, this variant meets criteria to be classified as pathogenic for Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency in an autosomal recessive manner based upon genetic and functional evidence. ACMG/AMP Criteria applied: PS 3_Supporting, PM2_Supporting, PM3_Very Strong -
Pathogenic, criteria provided, single submitter	curation	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 01, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	-	This c.1528G>C (p.Glu510Gln) variant has been identified in individuals affected with LCHAD deficiency and described, in the homozygous state, as the major disease-causing mutation in the alpha subunit of the mitochondrial trifunctional protein (IJlst et al. 1994). This variant is located in the catalytic site of the LCHAD domain. Functional studies show that although this variant results in intact mutant protein, its LCHAD activity is significantly reduced (Olpin et al. 2005). It is absent or not frequent in the population databases (0% in 1000 genomes and Exome Sequencing Project, and 0.18% in ExAc) and several computational algorithms predict this variant as deleterious. It has also been reported pathogenic by reputable mutation databases (ClinVar, Emory Genetics Laboratory, and HGMD). In sum, this c.1528G>C (p.Glu510Gln) variant is best described as a recessive pathogenic variant for LCHAD deficiency. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 02, 2020	Variant summary: HADHA c.1528G>C (p.Glu510Gln) results in a conservative amino acid change located in the 3-hydroxyacyl-CoA dehydrogenase, NAD binding domain (IPR006176) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0012 in 251462 control chromosomes (gnomAD). c.1528G>C has been reported in the literature in several homozygous and compound heterozygous individuals affected with Long Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency, and is a commonly known pathogenic variant. Publications also reported experimental evidence evaluating an impact on protein function, showing that in homozygous patient derived fibroblasts this variant results in <10% of normal LCHAD activity. Eleven other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Dec 28, 2021	ACMG classification criteria: PS3 supporting, PM3 very strong, PP3 supporting -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Inherited Metabolic Diseases, Karolinska University Hospital	Apr 07, 2021	- -

not provided

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	HADHA: PM3:Very Strong, PM2:Supporting, PP1, PP3, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Jun 17, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 27, 2024	PP3, PS3, PS4 -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 06, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 28, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Dec 12, 2020	PM3_Very_Strong, PS3 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 09, 2024	Functional studies found E510Q is associated with no detectable LCHAD enzyme activity (PMID: 8770876); 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: 19852779, 15902556, 25888220, 27117294, 28798025, 30029694, 34479707, 20583174, 25087612, 7846063, 10518281, 26109258, 7811722, 26024122, 27491397, 23868323, 26653362, 26676313, 28245050, 29095929, 28559085, 27334895, 31025818, 31479012, 31980526, 32827528, 34426522, 31589614, 33107778, 33204595, 35460704, 37443404, 37734845, 37549033, 32778825, 33726816, 21549624, 8770876, 35677112, 35383965, 35753512, 35782617, 35199468, 32253025, 34448047, 34732400) -

Mitochondrial trifunctional protein deficiency

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 1999	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Mar 20, 2020	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PS4,PP3. -

HADHA-related disorder

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 20, 2018	The HADHA c.1528G>C (p.Glu510Gln) variant, commonly known as Glu474Gln, has been reported in at least eight studies in association with HADHA-related disorders, including LCHAD deficiency and trifunctional protein deficiency. Across a selection of the available literature, the variant is found in at least 153 probands including at least 71 in a homozygous state, at least 22 in a compound heterozygous state, and 52 unaffected in a heterozygous state (Ijlst et al. 1994; Ijlst et al. 1997; Olpin et al. 2005; Piekutowska-Abramczuk et al. 2010; Joost et al. 2012; Boutron et al. 2011; Liewluck et al. 2013; Karall et al. 2015). The p.Glu510Gln variant was found in a compound heterozygous state with a premature termination codon on the second allele in at least twelve cases (Boutron et al. 2011). The p.Glu510Gln variant was absent from 110 control chromosomes and is reported at a frequency of 0.004032 in the European (Finnish) population of the Genome Aggregation Database. Functional testing of the p.Glu510Gln variant protein in yeast cells exhibited a loss of 3-hydroxyacyl-CoA dehydrogenase activity compared to wild type (Ijlst et al. 1996). In addition, functional testing in proband-specific retinal pigment epithelial cells found that cells carrying the p.Glu510Gln variant protein in a homozygous state were small, irregular in shape, with decreased pigmentation and had disorganized tight junctions inducing apoptosis (Polinati et al. 2015). Based on the collective evidence, the p.Glu510Gln variant is classified as pathogenic for HADHA-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Sep 18, 2024	The HADHA c.1528G>C variant is predicted to result in the amino acid substitution p.Glu510Gln. This variant has been reported as a recurrent cause of autosomal recessive long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency/mitochondrial trifunctional protein deficiency (Boutron et al. 2011. PubMed ID: 21549624; Karall et al. 2015. PubMed ID: 25888220; Boese et al. 2016. PubMed ID: 27491397). It has been interpreted as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/100085). This variant is reported in 0.39% of alleles in individuals of European (Finnish) descent in gnomAD. Taken together, this variant is interpreted as pathogenic. -

not specified

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Dec 17, 2018

The HADHA c.1528G>C; p.Glu510Gln variant (rs137852769) is the most common variant in individuals affected with long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency, found in either the homozygous or compound heterozygous state (IJlst 1994, reviewed in Piekutowska-Abramczuk 2010). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 100085), and is found in the general population with an overall allele frequency of 0.13% (366/282,830 alleles) in the Genome Aggregation Database. The glutamic acid at codon 510 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Functional analyses of the variant protein show normal protein expression but significant loss of enzyme activity (IJlst 1994, Olpin 2005). Based on available information, the p.Glu510Gln variant is considered to be pathogenic. References: IJlst L et al. Molecular basis of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: identification of the major disease-causing mutation in the alpha-subunit of the mitochondrial trifunctional protein. Biochim Biophys Acta. 1994 Dec 8;1215(3):347-50. Olpin SE et al. Biochemical, clinical and molecular findings in LCHAD and general mitochondrial trifunctional protein deficiency. J Inherit Metab Dis. 2005;28(4):533-44. Piekutowska-Abramczuk D et al. A comprehensive HADHA c.1528G>C frequency study reveals high prevalence of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency in Poland. J Inherit Metab Dis. 2010 Dec;33 Suppl 3:S373-7. -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 23, 2024

- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 07, 2014

- -

LCHAD deficiency with maternal acute fatty liver of pregnancy

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 1999

- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 510 of the HADHA protein (p.Glu510Gln). This variant is present in population databases (rs137852769, gnomAD 0.4%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency, or mitochondrial trifunctional protein deficiency (PMID: 7811722, 8739956, 11773547, 14630990, 15902556, 18408953, 19852779, 20583174, 21103935, 21549624, 23868323, 25888220, 26109258, 26653362, 27491397). This variant is also known as p.Glu474Gln or p.E474Q. ClinVar contains an entry for this variant (Variation ID: 100085). 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 HADHA protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects HADHA function (PMID: 8770876, 14630990, 15902556). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Pathogenic

0.45

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.93

D;.;.

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.96

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Pathogenic

0.53

MetaRNN

Benign

0.11

T;T;T

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.8

H;.;.

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-2.9

D;.;.

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

D;.;.

Sift4G

Pathogenic

0.0

D;.;.

Polyphen

1.0

D;.;.

Vest4

0.95

MVP

0.97

MPC

0.82

ClinPred

0.22

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.97

gMVP

0.88

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over