ClinVar Genomic variation as it relates to human health
NM_004453.4(ETFDH):c.770A>G (p.Tyr257Cys)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_004453.4(ETFDH):c.770A>G (p.Tyr257Cys)
Variation ID: 666174 Accession: VCV000666174.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 4q32.1 4: 158695582 (GRCh38) [ NCBI UCSC ] 4: 159616734 (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 Aug 14, 2019 Mar 30, 2024 Jan 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004453.4:c.770A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004444.2:p.Tyr257Cys missense NM_001281737.2:c.629A>G NP_001268666.1:p.Tyr210Cys missense NM_001281738.1:c.587A>G NP_001268667.1:p.Tyr196Cys missense NM_004453.2:c.770A>G NC_000004.12:g.158695582A>G NC_000004.11:g.159616734A>G NG_007078.2:g.28241A>G - Protein change
- Y196C, Y257C, Y210C
- Other names
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- Canonical SPDI
- NC_000004.12:158695581:A:G
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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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00005
Exome Aggregation Consortium (ExAC) 0.00007
The Genome Aggregation Database (gnomAD), exomes 0.00010
- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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ETFDH | - | - |
GRCh38 GRCh37 |
924 | 969 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (8) |
criteria provided, multiple submitters, no conflicts
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Jan 29, 2024 | RCV000824611.17 |
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
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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
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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
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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. |
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Pathogenic
(Jan 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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Multiple acyl-CoA dehydrogenase deficiency
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002058762.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Comment:
Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000666174, PMID:19758981, PS1_S). A … (more)
Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000666174, PMID:19758981, PS1_S). A different missense change at the same codon (p.Tyr257His) has been reported as pathogenic/likely pathogenic with strong evidence (PMID:27038534, PM5_M). The variantwas previously reported in trans with another pathogenic variant (NM_004453.4:c.250G>A) in this gene (3billion dataset, PM3_M). Functional studies provide supporting evidence of the variant having a damaging effect on the gene or gene product (PMID: 27935074) (PS3_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.812, 3CNET: 0.808, PP3_P). A missense variant is a common mechanism associated with Glutaric acidemia IIC (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0001, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Global developmental delay (present) , Abnormal facial shape (present) , Hepatic steatosis (present) , Generalized hypotonia (present) , Intellectual disability, mild (present) , Intellectual disability … (more)
Global developmental delay (present) , Abnormal facial shape (present) , Hepatic steatosis (present) , Generalized hypotonia (present) , Intellectual disability, mild (present) , Intellectual disability (present) (less)
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Pathogenic
(Mar 18, 2022)
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criteria provided, single submitter
Method: clinical testing
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Multiple acyl-CoA dehydrogenase deficiency
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002797546.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Feb 14, 2023)
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criteria provided, single submitter
Method: clinical testing
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Multiple acyl-CoA dehydrogenase deficiency
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004175837.1
First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023 |
Comment:
The missense c.770A>G(p.Tyr257Cys) variant in ETFDH gene has been reported previously in homozygous or compound heterozygous state in individual(s) affected with glutaric acidemia type II … (more)
The missense c.770A>G(p.Tyr257Cys) variant in ETFDH gene has been reported previously in homozygous or compound heterozygous state in individual(s) affected with glutaric acidemia type II or multiple acyl-CoA dehydrogenase deficiency (Zhao YW et al., 2018). This variant is reported with the allele frequency of 0.01% in the gnomAD Exomes and novel in 1000 Genomes. Functional studies provide supporting evidence of the variant having a damaging effect on the gene or gene product (Liang WC et al., 2017). This variant has been reported to the ClinVar database as Pathogenic by multiple submitters. The amino acid Tyr at position 257 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Tyr257Cys in ETFDH is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The variant is predicted as damaging by SIFT. For these reasons, this variant has been classified as Pathogenic. In the absence of another reportable variant, the molecular diagnosis is not confirmed. (less)
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Pathogenic
(Oct 25, 2023)
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criteria provided, single submitter
Method: clinical testing
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Multiple acyl-CoA dehydrogenase deficiency
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004194768.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jan 06, 2021)
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criteria provided, single submitter
Method: clinical testing
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Multiple acyl-CoA dehydrogenase deficiency
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002022217.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 29, 2024)
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criteria provided, single submitter
Method: clinical testing
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Multiple acyl-CoA dehydrogenase deficiency
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000965516.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 257 of the ETFDH protein … (more)
This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 257 of the ETFDH protein (p.Tyr257Cys). This variant is present in population databases (rs780015493, gnomAD 0.1%). This missense change has been observed in individual(s) with glutaric acidemia type II or multiple acyl-CoA dehydrogenase deficiency (PMID: 19758981, 21347544, 23628458, 24357026, 24522293, 29336361). 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: 666174). 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 with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jan 15, 2024)
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criteria provided, single submitter
Method: clinical testing
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Multiple acyl-CoA dehydrogenase deficiency
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004803391.1
First in ClinVar: Mar 30, 2024 Last updated: Mar 30, 2024 |
Comment:
Variant summary: ETFDH c.770A>G (p.Tyr257Cys) 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.770A>G (p.Tyr257Cys) 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 9.9e-05 in 251336 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ETFDH causing Glutaric Aciduria, Type 2c (9.9e-05 vs 0.0011), allowing no conclusion about variant significance. c.770A>G has been reported in the literature in multiple individuals affected with multiple acyl-CoA dehydrogenase deficiency (example: Xi_2014). 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: 24357026). ClinVar contains an entry for this variant (Variation ID: 666174). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Glutaric aciduria type 2
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001457084.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Muscle Magnetic Resonance Imaging for the Differentiation of Multiple Acyl-CoA Dehydrogenase Deficiency and Immune-mediated Necrotizing Myopathy. | Zhao YW | Chinese medical journal | 2018 | PMID: 29336361 |
Multiple acyl-CoA dehydrogenase deficiency (MADD) as a cause of late-onset treatable metabolic disease. | Béhin A | Revue neurologique | 2016 | PMID: 27038534 |
Riboflavin-responsive multiple Acyl-CoA dehydrogenation deficiency in 13 cases, and a literature review in mainland Chinese patients. | Zhu M | Journal of human genetics | 2014 | PMID: 24522293 |
Clinical features and ETFDH mutation spectrum in a cohort of 90 Chinese patients with late-onset multiple acyl-CoA dehydrogenase deficiency. | Xi J | Journal of inherited metabolic disease | 2014 | PMID: 24357026 |
Increased muscle coenzyme Q10 in riboflavin responsive MADD with ETFDH gene mutations due to secondary mitochondrial proliferation. | Wen B | Molecular genetics and metabolism | 2013 | PMID: 23628458 |
Molecular analysis of 51 unrelated pedigrees with late-onset multiple acyl-CoA dehydrogenation deficiency (MADD) in southern China confirmed the most common ETFDH mutation and high carrier frequency of c.250G>A. | Wang ZQ | Journal of molecular medicine (Berlin, Germany) | 2011 | PMID: 21347544 |
Riboflavin-responsive lipid-storage myopathy caused by ETFDH gene mutations. | Wen B | Journal of neurology, neurosurgery, and psychiatry | 2010 | PMID: 19758981 |
Text-mined citations for rs780015493 ...
HelpRecord last updated Apr 06, 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.