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.
ClinVar Genomic variation as it relates to human health
NM_004453.4(ETFDH):c.1001T>C (p.Leu334Pro)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(7)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
7
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_004453.4(ETFDH):c.1001T>C (p.Leu334Pro)
Variation ID: 199094 Accession: VCV000199094.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 4q32.1 4: 158699015 (GRCh38) [ NCBI UCSC ] 4: 159620167 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jun 28, 2015 Jun 17, 2024 Mar 24, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_004453.4:c.1001T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004444.2:p.Leu334Pro missense NM_001281737.2:c.860T>C NP_001268666.1:p.Leu287Pro missense NM_001281738.1:c.818T>C NP_001268667.1:p.Leu273Pro missense NC_000004.12:g.158699015T>C NC_000004.11:g.159620167T>C NG_007078.2:g.31674T>C Q16134:p.Leu334Pro - Protein change
- L334P, L273P, L287P
- Other names
- -
- Canonical SPDI
- NC_000004.12:158699014:T:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
The Genome Aggregation Database (gnomAD) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00004
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| ETFDH | - | - |
GRCh38 GRCh37 |
955 | 1000 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Mar 24, 2024 | RCV000180601.14 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jun 1, 2022 | RCV000723385.8 | |
|
Glutaric acidemia type 2C
|
Pathogenic (1) |
no assertion criteria provided
|
Jun 22, 2020 | RCV001826924.1 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Dec 10, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000233073.5
First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 3
Zygosity: Single Heterozygote
Sex: mixed
|
|
|
Likely pathogenic
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple acyl-CoA dehydrogenase deficiency
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000893658.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
|
|
Pathogenic
(Jul 28, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple acyl-CoA dehydrogenase deficiency
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002570772.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
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 … (more)
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. (less)
|
|
|
Pathogenic
(Jun 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001783941.3
First in ClinVar: Aug 14, 2021 Last updated: Mar 04, 2023 |
Comment:
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 … (more)
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) (less)
|
|
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Pathogenic
(Jan 10, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple acyl-CoA dehydrogenase deficiency
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000756265.7
First in ClinVar: Jun 28, 2015 Last updated: Feb 14, 2024 |
Comment:
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). … (more)
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. (less)
|
|
|
Pathogenic
(Mar 24, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple acyl-CoA dehydrogenase deficiency
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004194774.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Jun 22, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Glutaric acidemia type 2C
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002084858.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022 |
|
Comment:
Comment:
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)
Comment:
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.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
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.
Comment:
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)
Comment:
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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Molecular mechanisms of riboflavin responsiveness in patients with ETF-QO variations and multiple acyl-CoA dehydrogenation deficiency. | Cornelius N | Human molecular genetics | 2012 | PMID: 22611163 |
| ETFDH mutations as a major cause of riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency. | Olsen RK | Brain : a journal of neurology | 2007 | PMID: 17584774 |
| Glutaric acidemia type II: gene structure and mutations of the electron transfer flavoprotein:ubiquinone oxidoreductase (ETF:QO) gene. | Goodman SI | Molecular genetics and metabolism | 2002 | PMID: 12359134 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ETFDH | - | - | - | - |
Text-mined citations for rs377686388 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.