rs119458970

chr15-76274431-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_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. 12/20 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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 9.35

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]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a region_of_interest Domain II (size 128) in uniprot entity ETFA_HUMAN there are 5 pathogenic changes around while only 2 benign (71%) in NM_000126.4
• 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 id is 2594.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-76274431-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ETFA	NM_000126.4	c.797C>T	p.Thr266Met	missense_variant	9/12	ENST00000557943.6
ETFA	NM_001127716.2	c.650C>T	p.Thr217Met	missense_variant	8/11
ETFA	XR_007064434.1	n.878C>T		non_coding_transcript_exon_variant	9/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ETFA	ENST00000557943.6	c.797C>T	p.Thr266Met	missense_variant	9/12	1	NM_000126.4	P1
	ENST00000660046.1	n.240-499G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0000790 AC: 12 AN: 151974 Hom.: 0 Cov.: 32

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

GnomAD3 exomes AF: 0.0000444 AC: 11 AN: 247916 Hom.: 0 AF XY: 0.0000672 AC XY: 9 AN XY: 133946

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000715

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000603 AC: 88 AN: 1458926 Hom.: 0 Cov.: 30 AF XY: 0.0000551 AC XY: 40 AN XY: 725508

Gnomad4 AFR exome AF: 0.0000897

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000739

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome AF: 0.0000789 AC: 12 AN: 152092 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74354

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000109 Hom.: 0

Bravo AF: 0.0000718

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000494 AC: 6

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple acyl-CoA dehydrogenase deficiency Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 11, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 18, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 21, 2024	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). 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 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 04, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 19, 2020	Based on the classification scheme VCGS_Germline_v1.1.1, 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 -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	ETFA: PM3:Very Strong, PM2, PP3, PP4, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 30, 2020	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 20, 2016	- -

Glutaric acidemia IIa Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2003

- -

ETFA-related condition Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 31, 2024

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	D
BayesDel_noAF	Pathogenic	0.53
Cadd	Pathogenic	34
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	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	5.1	H;.;.;.;.
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.7	D;D;D;D;D
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	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.86

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

Other links and lift over

dbSNP: rs119458970; hg19: chr15-76566772;