rs119458970

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_000126.4(ETFA):c.797C>T(p.Thr266Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000621 in 1,611,018 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T266T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000060 ( 0 hom. )

Consequence

ETFA
NM_000126.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 9.35

Publications

14 publications found

Variant links:

Genes affected

ETFA (HGNC:3481): (electron transfer flavoprotein subunit alpha) ETFA participates in catalyzing the initial step of the mitochondrial fatty acid beta-oxidation. It shuttles electrons between primary flavoprotein dehydrogenases and the membrane-bound electron transfer flavoprotein ubiquinone oxidoreductase. Defects in electron-transfer-flavoprotein have been implicated in type II glutaricaciduria in which multiple acyl-CoA dehydrogenase deficiencies result in large excretion of glutaric, lactic, ethylmalonic, butyric, isobutyric, 2-methyl-butyric, and isovaleric acids. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ETFA Gene-Disease associations (from GenCC):

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

ETFA links:

ENSG00000287503 (HGNC:):

ENSG00000287503 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.938

PP5

Variant 15-76274431-G-A is Pathogenic according to our data. Variant chr15-76274431-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 2594.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
ETFA	NM_000126.4 link	c.797C>T	p.Thr266Met	missense_variant	Exon 9 of 12	ENST00000557943.6	NP_000117.1
ETFA	NM_001127716.2 link	c.650C>T	p.Thr217Met	missense_variant	Exon 8 of 11		NP_001121188.1
ETFA	XR_007064434.1 link	n.878C>T		non_coding_transcript_exon_variant	Exon 9 of 12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ETFA	ENST00000557943.6 link	c.797C>T	p.Thr266Met	missense_variant	Exon 9 of 12	1	NM_000126.4	ENSP00000452762.1

Frequencies

GnomAD3 genomes

AF:

0.0000790

AC:

AN:

151974

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000444

AC:

AN:

247916

AF XY:

0.0000672

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000292

Gnomad ASJ exome

AF:

0.000101

Gnomad EAS exome

AF:

0.0000545

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000715

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000603

AC:

AN:

1458926

Hom.:

Cov.:

AF XY:

0.0000551

AC XY:

AN XY:

725508

show subpopulations

African (AFR)

AF:

0.0000897

AC:

AN:

33450

American (AMR)

AF:

0.00

AC:

AN:

44480

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26024

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39664

South Asian (SAS)

AF:

0.00

AC:

AN:

85700

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53258

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000739

AC:

AN:

1110318

Other (OTH)

AF:

0.0000332

AC:

AN:

60268

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

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:

0.0000789

AC:

AN:

152092

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41482

American (AMR)

AF:

0.00

AC:

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10562

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

68006

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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:

0.0000988

Hom.:

Bravo

AF:

0.0000718

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Multiple acyl-CoA dehydrogenase deficiency

Pathogenic:7

May 11, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The EFTA c.797C>T (p.Thr266Met) missense variant has been described in three studies in which it is found in a total of six patients with multiple acyl-CoA dehydrogenase deficiency, including in two in a homozygous state, in three in a compound heterozygous state, and in one in a heterozygous state (Freneaux et. al. 1992; Olsen et. al. 2003; Pontoizeau et al. 2015). The p.Thr266Met was absent from 54 controls and is reported at a frequency of 0.00008 in the European (non-Finnish) population of the Exome Aggregation Consortium. The Thr266 residue is conserved. Functional studies demonstrated that the p.Thr266Met variant protein showed an altered flavin environment and reduced enzyme activity (Salazar et. al. 1997). Fatty acid oxidation assays in patient fibroblasts showed the variant resulted in a severely defective beta-oxidation flux, with 3% to 26% of oxidation compared to controls (Freneaux et al. 1992; Olsen et. al. 2003). Based on the evidence, the p.Thr266Met variant is classified as pathogenic for multiple acyl-CoA dehydrogenase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Oct 10, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with recessive glutaric acidemia IIA (MIM#231680). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from threonine to methionine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 12 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the nucleotide phosphate binding region in the electron transfer flavoprotein FAD-binding domain (Decipher; Protein DataBank). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in at least 10 individuals with neonatal or early-onset autosomal recessive glutaric acidemia IIA (MIM#231680) (ClinVar, PMIDs: 1430199, 26409463, 31268564). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Sep 16, 2020

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 10, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 18, 2023

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: ETFA c.797C>T (p.Thr266Met) results in a non-conservative amino acid change located in the C-terminal domain (IPR014731) of 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 4.4e-05 in 247916 control chromosomes (gnomAD). This frequency is not higher than estimated for a pathogenic variant in ETFA causing Glutaric Aciduria, Type 2a (4.4e-05 vs 0.0011), allowing no conclusion about variant significance. c.797C>T has been reported in the literature in multiple individuals affected with Glutaric Aciduria, Type 2a (Freneaux_1992, van Rijt_2019). These data indicate that the variant is very likely to be associated with disease. Experimental evidence demonstrated the variant affects protein function (Salazar_1997, van Rijt_2019). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 266 of the ETFA protein (p.Thr266Met). This variant is present in population databases (rs119458970, gnomAD 0.01%). This missense change has been observed in individual(s) with ETFA-related conditions (PMID: 1430199, 12815589, 16510302, 26409463). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 2594). 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) indicates that this missense variant is expected to disrupt ETFA protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ETFA function (PMID: 9334218). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:3

Sep 30, 2020

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Expression studies demonstrate a decrease in enzyme activity (Salazar et al., 1997); Not observed at a significant frequency in large population cohorts (gnomAD); 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: 2320399, 16510302, 12815589, 11524729, 32778825, 20674745, 1430199, 9334218, 26409463, 18289905, 20151199, 31331668, 31268564, 31980526, 34470039, 34426522, 31904027) -

Apr 20, 2016

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ETFA: PM3:Very Strong, PM2, PP3, PP4, PS3:Supporting -

Glutaric acidemia IIa

Pathogenic:1

Jul 01, 2003

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Inborn genetic diseases

Pathogenic:1

May 23, 2025

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.797C>T (p.T266M) alteration is located in exon 9 (coding exon 9) of the ETFA gene. This alteration results from a C to T substitution at nucleotide position 797, causing the threonine (T) at amino acid position 266 to be replaced by a methionine (M). Based on data from gnomAD, the T allele has an overall frequency of 0.004% (12/279316) total alleles studied. The highest observed frequency was 0.01% (1/10234) of Ashkenazi Jewish alleles. This variant has been identified in the homozygous state and/or in conjunction with other ETFA variant(s) in individual(s) with features consistent with glutaric acidemia II (van Rijt, 2020; van Rijt, 2019; Pontoizeau, 2016; Schiff, 2006; Freneaux, 1992). This amino acid position is highly conserved in available vertebrate species. Functional studies suggest a loss of function effect; however, additional evidence is needed to confirm these findings (Salazar, 1997; Augustin, 2018). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

ETFA-related disorder

Pathogenic:1

Jan 31, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The ETFA c.797C>T variant is predicted to result in the amino acid substitution p.Thr266Met. This variant is the most commonly reported ETFA pathogenic variant that is causative for glutaric acidemia type II; it has been reported in the homozygous or compound heterozygous state with a second pathogenic variant in multiple affected patients (e.g., Schiff et al. 2006. PubMed ID: 16510302; Yıldız et al. 2019. PubMed ID: 31331668; van Rijt et al. 2020. PubMed ID: 31904027). The p.Thr266Met amino acid substitution has been reported to disrupt the FAD binding site, and results in a great decrease in ETF activity (Schiff et al. 2006. PubMed ID: 16510302; Henriques et al. 2010. PubMed ID: 20674745). Patients homozygous for the c.797C>T (p.Thr266Met) variant have been reported to present with a severe neonatal form of glutaric acidemia type II (Schiff et al. 2006. PubMed ID: 16510302). Based on these observations, we classify this variant as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.90

D;.;D;.;D

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.1

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D;D;D;D

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.94

D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

5.1

H;.;.;.;.

PhyloP100

9.4

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-5.7

D;D;D;D;D

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D

Polyphen

1.0

D;.;.;.;.

Vest4

0.86

MVP

0.98

MPC

1.2

ClinPred

0.92

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.94

gMVP

0.86

Mutation Taster

=9/91

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over