rs779896449

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_004453.4(ETFDH):c.413T>G(p.Leu138Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000033 in 1,544,460 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. L138F) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000035 ( 0 hom. )

Consequence

ETFDH
NM_004453.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 6.00

Publications

6 publications found

Variant links:

Genes affected

ETFDH (HGNC:3483): (electron transfer flavoprotein dehydrogenase) This gene encodes a component of the electron-transfer system in mitochondria and is essential for electron transfer from a number of mitochondrial flavin-containing dehydrogenases to the main respiratory chain. Mutations in this gene are associated with glutaric acidemia. Alternatively spliced transcript variants that encode distinct isoforms have been observed. [provided by RefSeq, Aug 2013]

ETFDH Gene-Disease associations (from GenCC):

multiple acyl-CoA dehydrogenase deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, Ambry Genetics

ETFDH links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 19 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_004453.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr4-158684598-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2151992.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 86 curated pathogenic missense variants (we use a threshold of 10). The gene has 11 curated benign missense variants. Gene score misZ: 0.39306 (below the threshold of 3.09). Trascript score misZ: 0.49505 (below the threshold of 3.09). GenCC associations: The gene is linked to multiple acyl-CoA dehydrogenase deficiency.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.989

PP5

Variant 4-158684599-T-G is Pathogenic according to our data. Variant chr4-158684599-T-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 431962.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
ETFDH	NM_004453.4 link	c.413T>G	p.Leu138Arg	missense_variant	Exon 4 of 13	ENST00000511912.6	NP_004444.2
ETFDH	NM_001281737.2 link	c.272T>G	p.Leu91Arg	missense_variant	Exon 3 of 12		NP_001268666.1
ETFDH	NM_001281738.1 link	c.230T>G	p.Leu77Arg	missense_variant	Exon 2 of 11		NP_001268667.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ETFDH	ENST00000511912.6 link	c.413T>G	p.Leu138Arg	missense_variant	Exon 4 of 13	1	NM_004453.4	ENSP00000426638.1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000798

AC:

AN:

250696

AF XY:

0.00000737

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000352

AC:

AN:

1392256

Hom.:

Cov.:

AF XY:

0.0000301

AC XY:

AN XY:

696934

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32044

American (AMR)

AF:

0.00

AC:

AN:

44556

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25700

East Asian (EAS)

AF:

0.00

AC:

AN:

39336

South Asian (SAS)

AF:

0.00

AC:

AN:

84574

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53376

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5638

European-Non Finnish (NFE)

AF:

0.0000448

AC:

AN:

1048892

Other (OTH)

AF:

0.0000344

AC:

AN:

58140

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.444

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41448

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5206

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000406

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Multiple acyl-CoA dehydrogenase deficiency

Pathogenic:4

Nov 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 138 of the ETFDH protein (p.Leu138Arg). This variant is present in population databases (rs779896449, gnomAD 0.002%). This missense change has been observed in individuals with multiple acyl-CoA dehydrogenase (PMID: 12359134, 15669683, 32925727). ClinVar contains an entry for this variant (Variation ID: 431962). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ETFDH protein function. Experimental studies have shown that this missense change affects ETFDH function (PMID: 22611163). For these reasons, this variant has been classified as Pathogenic. -

Mar 20, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 29, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 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: ETFDH c.413T>G (p.Leu138Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250696 control chromosomes (gnomAD). c.413T>G has been reported in the literature in individuals affected with Glutaric aciduria, type 2 (Goodman_2002, Olsen_2004, Cornelius_2012). These data indicate that the variant may be associated with disease. A functional study, Cornelius_2012, found the variant to impact enzyme activity and protein stability. Two ClinVar submissions (evaluation after 2014) cite the variant once as pathogenic and once as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Inborn genetic diseases

Pathogenic:1

Jan 24, 2018

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:1

May 23, 2017

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The L138R missense variant in the ETFDH gene has been reported previously in association with glutaric aciduria II (GAII) (Olsen et al. 2004; Cornelius et al. 2012; Goodman et al. 2002). Expression studies show that L138R profoundly reduces the amount and activity of the electron transfer flavoprotein-ubiquinone oxidoreductase enzyme with no significant response to increasing concentrations of riboflavin (Cornelius et al. 2012). The L138R variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The L138R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, we interpret L138R to be a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.61

D;.

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Pathogenic

0.82

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.2

H;.

PhyloP100

6.0

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-5.1

D;D

REVEL

Pathogenic

0.98

Sift

Uncertain

0.0040

D;D

Sift4G

Uncertain

0.0050

D;D

Polyphen

1.0

D;.

Vest4

0.98

MutPred

0.88

Gain of disorder (P = 0.0172);.;

MVP

0.99

MPC

0.60

ClinPred

0.99

GERP RS

5.8

Varity_R

0.81

gMVP

0.93

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over