rs387907170

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong

The NM_004453.4(ETFDH):c.1130T>C(p.Leu377Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,978 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 (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ETFDH
NM_004453.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 8.02

Publications

13 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 17 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_004453.4

PM2

Very rare variant in population databases, with high coverage;

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, 0.986

PP5

Variant 4-158703436-T-C is Pathogenic according to our data. Variant chr4-158703436-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 31601.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ETFDH	NM_004453.4 link	c.1130T>C	p.Leu377Pro	missense_variant	Exon 10 of 13	ENST00000511912.6	NP_004444.2	Q16134-1B4DEQ0
ETFDH	NM_001281737.2 link	c.989T>C	p.Leu330Pro	missense_variant	Exon 9 of 12		NP_001268666.1	Q16134-3B4DEQ0
ETFDH	NM_001281738.1 link	c.947T>C	p.Leu316Pro	missense_variant	Exon 8 of 11		NP_001268667.1	B4DEQ0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ETFDH	ENST00000511912.6 link	c.1130T>C	p.Leu377Pro	missense_variant	Exon 10 of 13	1	NM_004453.4	ENSP00000426638.1		Q16134-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251294

AF XY:

0.00

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:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1458978

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726060

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33402

American (AMR)

AF:

0.00

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26108

East Asian (EAS)

AF:

0.00

AC:

AN:

39610

South Asian (SAS)

AF:

0.00

AC:

AN:

86192

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

9.01e-7

AC:

AN:

1109488

Other (OTH)

AF:

0.0000166

AC:

AN:

60294

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

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Multiple acyl-CoA dehydrogenase deficiency

Pathogenic:8

Aug 18, 2022

Kariminejad - Najmabadi Pathology & Genetics Center

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM1, PM2, PP3, PP5 -

Jun 17, 2022

MGZ Medical Genetics Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 19, 2023

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 16, 2024

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.1130T>C (p.Leu377Pro) 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 4e-06 in 251294 control chromosomes. c.1130T>C has been reported in the literature in multiple individuals affected with Glutaric Aciduria, Type 2c (e.g., Nilipour_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 32007756). ClinVar contains an entry for this variant (Variation ID: 31601). Based on the evidence outlined above, the variant was classified as pathogenic. -

Jun 02, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

For these reasons, this variant has been classified as Pathogenic. 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 not expected to disrupt ETFDH protein function. ClinVar contains an entry for this variant (Variation ID: 31601). This missense change has been observed in individual(s) with multiple Acyl-CoA dehydrogenase deficiency (PMID: 17412732, 29339009, 29376578, 31331668). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 377 of the ETFDH protein (p.Leu377Pro). This variant is present in population databases (rs387907170, gnomAD 0.0009%). -

May 16, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 24, 2017

Institute of Human Genetics Munich, TUM University Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 22, 2021

Genome-Nilou Lab

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Pathogenic:1

Jul 21, 2014

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1130T>C (p.L377P) alteration is located in exon 10 (coding exon 10) of the ETFDH gene. This alteration results from a T to C substitution at nucleotide position 1130, causing the leucine (L) at amino acid position 377 to be replaced by a proline (P). Based on data from the NHLBI Exome Sequencing Project (ESP), the c.1130T>C alteration was not observed among 6,503 individuals tested (0.0%). Allele frequency data for this nucleotide position are not currently available from the 1000 Genomes Project and the alteration is not currently listed in the Database of Single Nucleotide Polymorphisms (dbSNP). Though some variants may appear to be rare due to database-specific ethnic underrepresentation, rare missense alleles commonly exhibit a deleterious effect on protein function (Kryukov, 2007; Tennessen, 2012). REFERENCES: Kryukov GV, et al. (2007) Am J Hum Genet 80:727-739. Tennessen JA, et al. (2012) Science 337(64):64-69. Reported in association with CoQ10 deficiency (Gempel (2007) Brain 130, 2037). This amino acid position is completely conserved in available vertebrate species. This alteration is predicted to be probably damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively. Based on the available evidence, this alteration is classified as pathogenic. -

Glutaric acidemia type 2C

Pathogenic:1

Sep 11, 2020

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Glutaric acidemia iic, late-onset

Pathogenic:1

Aug 01, 2007

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.46

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.65

D;.

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Pathogenic

0.58

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Uncertain

0.76

MutationAssessor

Pathogenic

3.1

M;.

PhyloP100

8.0

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-6.3

D;D

REVEL

Pathogenic

0.92

Sift

Benign

0.048

D;T

Sift4G

Uncertain

0.040

D;D

Polyphen

1.0

D;.

Vest4

0.99

MutPred

0.91

Gain of disorder (P = 0.0178);.;

MVP

0.98

MPC

0.63

ClinPred

0.99

GERP RS

5.4

Varity_R

0.92

gMVP

0.99

Mutation Taster

=0/100

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over