NM_004453.4(ETFDH):c.121C>T (p.Arg41Ter) AND Multiple acyl-CoA dehydrogenase deficiency

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jan 29, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000699705.11

Allele description [Variation Report for NM_004453.4(ETFDH):c.121C>T (p.Arg41Ter)]

NM_004453.4(ETFDH):c.121C>T (p.Arg41Ter)

Gene:

ETFDH:electron transfer flavoprotein dehydrogenase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

4q32.1

Genomic location:

Preferred name:

NM_004453.4(ETFDH):c.121C>T (p.Arg41Ter)

HGVS:

NC_000004.12:g.158680553C>T
NG_007078.2:g.13212C>T
NM_001281737.2:c.35-1642C>T
NM_004453.4:c.121C>TMANE SELECT
NP_004444.2:p.Arg41Ter
NC_000004.11:g.159601705C>T
NM_004453.3:c.121C>T

Protein change:

R41*

Links:

dbSNP: rs773668457

NCBI 1000 Genomes Browser:

rs773668457

Molecular consequence:

NM_001281737.2:c.35-1642C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_004453.4:c.121C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Multiple acyl-CoA dehydrogenase deficiency (MADD)
Synonyms:: GA II; Ethylmalonic-adipicaciduria; Glutaric aciduria, type 2; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009282; MedGen: C0268596; Orphanet: 26791; OMIM: 231680

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000828428	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 29, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 16510302, 23785301, 12359134, 24190796, 28492532
SCV001452017	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV004100083	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Sep 22, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000828428

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 29, 2024)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV001452017

Natera, Inc.

no assertion criteria provided

Pathogenic
(Sep 16, 2020)

germline

clinical testing

SCV004100083

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Sep 22, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Electron transfer flavoprotein deficiency: functional and molecular aspects.

Schiff M, Froissart R, Olsen RK, Acquaviva C, Vianey-Saban C.

Mol Genet Metab. 2006 Jun;88(2):153-8. Epub 2006 Feb 28.

PubMed [citation]

PMID:: 16510302

Multi-organ abnormalities and mTORC1 activation in zebrafish model of multiple acyl-CoA dehydrogenase deficiency.

Kim SH, Scott SA, Bennett MJ, Carson RP, Fessel J, Brown HA, Ess KC.

PLoS Genet. 2013 Jun;9(6):e1003563. doi: 10.1371/journal.pgen.1003563. Epub 2013 Jun 13.

PubMed [citation]

PMID:: 23785301
PMCID:: PMC3681725

See all PubMed Citations (5)

Details of each submission

From Invitae, SCV000828428.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change creates a premature translational stop signal (p.Arg41*) in the ETFDH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ETFDH are known to be pathogenic (PMID: 16510302, 23785301). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with glutaric acidemia type II (PMID: 12359134, 24190796). ClinVar contains an entry for this variant (Variation ID: 577047). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV001452017.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004100083.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

Variant summary: ETFDH c.121C>T (p.Arg41X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4e-06 in 251316 control chromosomes. c.121C>T has been reported in the literature in individuals affected with Glutaric Aciduria (e.g. Goodman_2002). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 12359134). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Feb 28, 2024

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