ClinVar Genomic variation as it relates to human health
NM_000016.6(ACADM):c.881G>C (p.Arg294Thr)
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_000016.6(ACADM):c.881G>C (p.Arg294Thr)
Variation ID: 226075 Accession: VCV000226075.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p31.1 1: 75750482 (GRCh38) [ NCBI UCSC ] 1: 76216167 (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 May 21, 2016 Jun 17, 2024 Mar 25, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000016.6:c.881G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000007.1:p.Arg294Thr missense NM_000016.5:c.881G>C NM_001127328.3:c.893G>C NP_001120800.1:p.Arg298Thr missense NM_001286042.2:c.773G>C NP_001272971.1:p.Arg258Thr missense NM_001286043.2:c.980G>C NP_001272972.1:p.Arg327Thr missense NM_001286044.2:c.314G>C NP_001272973.1:p.Arg105Thr missense NC_000001.11:g.75750482G>C NC_000001.10:g.76216167G>C NG_007045.2:g.31125G>C LRG_838:g.31125G>C LRG_838t1:c.881G>C - Protein change
- R294T, R298T, R105T, R258T, R327T
- Other names
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- Canonical SPDI
- NC_000001.11:75750481:G: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.
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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), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
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 | ||
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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
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. |
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ACADM | - | - |
GRCh38 GRCh37 |
891 | 923 |
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
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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/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Mar 25, 2024 | RCV000211542.17 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Sep 29, 2016 | RCV000421774.1 |
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
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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
(Feb 20, 2015)
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criteria provided, single submitter
Method: clinical testing
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Medium-chain acyl-coenzyme A dehydrogenase deficiency
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000268460.1
First in ClinVar: May 21, 2016 Last updated: May 21, 2016 |
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Likely pathogenic
(Sep 29, 2016)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000521112.3
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
Comment:
The R294T missense variant in the ACADM gene has been reported in a patient with MCAD deficiency who also harbored the common pathogenic K329E variant … (more)
The R294T missense variant in the ACADM gene has been reported in a patient with MCAD deficiency who also harbored the common pathogenic K329E variant on the opposite ACADM allele (in trans) (McKinney et al. 2004). R294T was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R294T variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, we interpret the R294T variant to be likely pathogenic. (less)
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Likely pathogenic
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Medium-chain acyl-coenzyme A dehydrogenase deficiency
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000894143.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Likely pathogenic
(Jun 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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Medium-chain acyl-coenzyme A dehydrogenase deficiency
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004020531.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
Variant summary: ACADM c.881G>C (p.Arg294Thr) results in a non-conservative amino acid change located in the C-terminal domain (IPR009075) of the encoded protein sequence. Four of … (more)
Variant summary: ACADM c.881G>C (p.Arg294Thr) results in a non-conservative amino acid change located in the C-terminal domain (IPR009075) of the encoded protein sequence. Four 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 250574 control chromosomes (i.e. 1 allele in gnomAD v2.1). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.881G>C has been reported in the literature in at least 3 individuals diagnosed with Medium Chain Acyl-CoA Dehydrogenase Deficiency (MCADD) (e.g. McKinney_2004, Adhikari_2020, Li_2022). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, nearby missense changes have been reported in affected individuals (HGMD), indicating a functional importance for the protein region. The following publications have been ascertained in the context of this evaluation (PMID: 32778825, 36068006, 15171998, 30675864). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic (n=2)/likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Pathogenic
(Oct 16, 2023)
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criteria provided, single submitter
Method: clinical testing
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Medium-chain acyl-coenzyme A dehydrogenase deficiency
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002247402.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 294 of the ACADM protein (p.Arg294Thr). … (more)
This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 294 of the ACADM protein (p.Arg294Thr). This variant is present in population databases (rs779759347, gnomAD 0.0009%). This missense change has been observed in individual(s) with MCAD deficiency (PMID: 15171998, 30675864). ClinVar contains an entry for this variant (Variation ID: 226075). 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 ACADM protein function. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 25, 2024)
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criteria provided, single submitter
Method: clinical testing
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Medium-chain acyl-coenzyme A dehydrogenase deficiency
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004217411.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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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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Newborn screening and genetic variation of medium chain acyl-CoA dehydrogenase deficiency in the Chinese population. | Li YY | Journal of pediatric endocrinology & metabolism : JPEM | 2022 | PMID: 36068006 |
The role of exome sequencing in newborn screening for inborn errors of metabolism. | Adhikari AN | Nature medicine | 2020 | PMID: 32778825 |
[Medium-chain acyl-CoA dehydrogenase deficiency: neonatal screening and follow-uP]. | Tong F | Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics | 2019 | PMID: 30675864 |
Rapid, comprehensive screening of the human medium chain acyl-CoA dehydrogenase gene. | McKinney JT | Molecular genetics and metabolism | 2004 | PMID: 15171998 |
Text-mined citations for rs779759347 ...
HelpRecord 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.