rs377686388

Variant names:

• chr4-158699015-T-C
• rs377686388
• NM_004453.4:c.1001T>C

Your query was ambiguous. Multiple possible variants found:

• chr4-158699015-T-C
• chr4-158699015-T-G

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_004453.4(ETFDH):​c.1001T>C​(p.Leu334Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000832 in 1,609,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/22 in silico tools predict a damaging 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. L334R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000090 (0 hom.)
• Consequence: ETFDH NM_004453.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 8.02
• Publications: 3 publications found

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

ACMG classification

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

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 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 chr4-158699015-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1499645.
• 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, 0.958
• PP5: Variant 4-158699015-T-C is Pathogenic according to our data. Variant chr4-158699015-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 199094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004453.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ETFDH	NM_004453.4	MANE Select	c.1001T>C	p.Leu334Pro	missense	Exon 9 of 13	NP_004444.2
	ETFDH	NM_001281737.2		c.860T>C	p.Leu287Pro	missense	Exon 8 of 12	NP_001268666.1
	ETFDH	NM_001281738.1		c.818T>C	p.Leu273Pro	missense	Exon 7 of 11	NP_001268667.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ETFDH	ENST00000511912.6	TSL:1 MANE Select	c.1001T>C	p.Leu334Pro	missense	Exon 9 of 13	ENSP00000426638.1
	ETFDH	ENST00000506422.1	TSL:1	n.87-4408T>C		intron	N/A
	ETFDH	ENST00000684622.1		c.1001T>C	p.Leu334Pro	missense	Exon 9 of 14	ENSP00000507546.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152202 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000239 AC: 6 AN: 251366 AF XY: 0.0000368

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: 0.0000440

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000899 AC: 131 AN: 1457648 Hom.: 0 Cov.: 29 AF XY: 0.0000827 AC XY: 60 AN XY: 725486

African (AFR) AF: 0.00 AC: 0 AN: 33392

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.00 AC: 0 AN: 86160

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.000112 AC: 124 AN: 1108140

Other (OTH) AF: 0.000116 AC: 7 AN: 60294

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152202 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74346

African (AFR) AF: 0.00 AC: 0 AN: 41464

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000727 Hom.: 0

Bravo AF: 0.0000378

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple acyl-CoA dehydrogenase deficiency Pathogenic:4

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 24, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 10, 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 proline, which is neutral and non-polar, at codon 334 of the ETFDH protein (p.Leu334Pro). This variant is present in population databases (rs377686388, gnomAD 0.006%). This missense change has been observed in individuals with multiple acyl-CoA dehydrogenase deficiency (PMID: 12359134, 17584774). ClinVar contains an entry for this variant (Variation ID: 199094). 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 ETFDH protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ETFDH function (PMID: 22611163). For these reasons, this variant has been classified as Pathogenic.

Jul 28, 2022

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.1001T>C (p.Leu334Pro) 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 2.4e-05 in 251366 control chromosomes. c.1001T>C has been reported in the literature in multiple individuals affected with Glutaric Aciduria, Type 2c (examples: Goodman_2002, Olsen_2007). These data indicate that the variant is very likely to be associated with disease. Expression studies showed that the variant results in profoundly reduced amount of protein amount and activity, with no significant response to increasing concentrations of riboflavin in culture media (Cornelius_2012). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

not provided Pathogenic:2

Dec 10, 2014

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 01, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Expression studies found that L334P is associated with profoundly decreased ETF-QO protein levels and enzyme activities compared to wild-type and that there was no significant improvement in activity in response to increasing riboflavin levels (Cornelius et al. 2012); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 12359134, 17584774, 22611163, 28263315, 31980526, 31904027)

Inborn genetic diseases Pathogenic:1

Oct 25, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1001T>C (p.L334P) alteration is located in exon 9 (coding exon 9) of the ETFDH gene. This alteration results from a T to C substitution at nucleotide position 1001, causing the leucine (L) at amino acid position 334 to be replaced by a proline (P). Based on data from gnomAD, the C allele has an overall frequency of 0.003% (8/282776) total alleles studied. The highest observed frequency was 0.014% (1/7222) of Other alleles. This alteration was detected in the homozygous state, and in conjunction with another alteration in ETFDH, in multiple individuals with ETFDH-related glutaric acidemia II (Olsen, 2007; Ambrose, 2022; Goodman, 2002). This amino acid position is well conserved in available vertebrate species. In an assay testing ETFDH function, this variant showed a functionally abnormal result (Cornelius, 2012). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.

Glutaric acidemia type 2C Pathogenic:1

Jun 22, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.63	D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Pathogenic	4.1	H
PhyloP100		8.0
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.9	D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MVP		1.0
MPC		0.63
ClinPred		1.0	D
GERP RS		3.5
Varity_R		0.89
gMVP		0.98
Mutation Taster		=31/69	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs377686388; hg19: chr4-159620167;