2-26195184-C-G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 13P and 1B. PS3PP3PP5_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 Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000538038: Functional studies show that although this variant results in intact mutant protein, its LCHAD activity is significantly reduced (Olpin et al. 2005)." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. E510E) has been classified as Uncertain significance.

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/Likely pathogenic criteria provided, multiple submitters, no conflicts P:31

Conservation

PhyloP100: 7.76

Publications

127 publications found

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 was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000538038: Functional studies show that although this variant results in intact mutant protein, its LCHAD activity is significantly reduced (Olpin et al. 2005).; SCV000695940: 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.; SCV000967670: In vitro functional studies provide some evidence that the p.Glu510Gln variant may impact protein function (Polinati 2015).; SCV000238888: Functional studies found E510Q is associated with no detectable LCHAD enzyme activity (PMID: 8770876);; SCV002051516: PS3; SCV000645773: Experimental studies have shown that this missense change affects HADHA function (PMID: 8770876, 14630990, 15902556).; SCV000914918: 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).; SCV001159663: Functional analyses of the variant protein show normal protein expression but significant loss of enzyme activity (IJlst 1994, Olpin 2005).

PP3

Multiple lines of computational evidence support a deleterious effect 10: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, M_CAP, MutationAssessor, phyloP100way_vertebrate, REVEL, 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/Likely_pathogenic. ClinVar VariationId is 100085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000182.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HADHA	NM_000182.5	MANE Select	c.1528G>C	p.Glu510Gln	missense	Exon 15 of 20	NP_000173.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HADHA	ENST00000380649.8	TSL:1 MANE Select	c.1528G>C	p.Glu510Gln	missense	Exon 15 of 20	ENSP00000370023.3	P40939-1
HADHA	ENST00000942149.1		c.1693G>C	p.Glu565Gln	missense	Exon 16 of 21	ENSP00000612208.1
HADHA	ENST00000942146.1		c.1624G>C	p.Glu542Gln	missense	Exon 15 of 20	ENSP00000612205.1

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

GnomAD2 exomes

AF:

0.00123

AC:

309

AN:

251462

AF XY:

0.00113

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 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

African (AFR)

AF:

0.000239

AC:

AN:

33454

American (AMR)

AF:

0.000827

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.000104

AC:

AN:

86214

European-Finnish (FIN)

AF:

0.00464

AC:

248

AN:

53420

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00148

AC:

1639

AN:

1110466

Other (OTH)

AF:

0.00109

AC:

AN:

60336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

106

212

319

425

531

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

124

186

248

310

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00101

AC:

153

AN:

152132

Hom.:

Cov.:

AF XY:

0.00117

AC XY:

AN XY:

74370

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41494

American (AMR)

AF:

0.000459

AC:

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00273

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00162

AC:

110

AN:

67998

Other (OTH)

AF:

0.000949

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency (12)

not provided (8)

Mitochondrial trifunctional protein deficiency (3)

HADHA-related disorder (2)

Inborn genetic diseases (1)

LCHAD deficiency with maternal acute fatty liver of pregnancy (1)

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

Metabolic disease (1)

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

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Pathogenic

0.45

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.93

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.96

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.53

MetaRNN

Benign

0.11

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.8

PhyloP100

7.8

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-2.9

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

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

Mutation Taster

=10/90

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over