ClinVar Genomic variation as it relates to human health
NM_000016.6(ACADM):c.134A>G (p.Gln45Arg)
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.134A>G (p.Gln45Arg)
Variation ID: 281077 Accession: VCV000281077.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p31.1 1: 75732659 (GRCh38) [ NCBI UCSC ] 1: 76198344 (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 Dec 6, 2016 Feb 14, 2024 Nov 29, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000016.6:c.134A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000007.1:p.Gln45Arg missense NM_001127328.3:c.146A>G NP_001120800.1:p.Gln49Arg missense NM_001286042.2:c.26A>G NP_001272971.1:p.Gln9Arg missense NM_001286043.2:c.134A>G NP_001272972.1:p.Gln45Arg missense NM_001286044.2:c.-252A>G 5 prime UTR NC_000001.11:g.75732659A>G NC_000001.10:g.76198344A>G NG_007045.2:g.13302A>G LRG_838:g.13302A>G LRG_838t1:c.134A>G LRG_838p1:p.Gln45Arg - Protein change
- Q45R, Q9R, Q49R
- Other names
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- Canonical SPDI
- NC_000001.11:75732658: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.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
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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ACADM | - | - |
GRCh38 GRCh37 |
859 | 891 |
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
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 (4) |
criteria provided, multiple submitters, no conflicts
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Nov 29, 2023 | RCV000333494.12 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jul 6, 2017 | RCV000723521.4 |
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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Likely pathogenic
(Jul 06, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000331231.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(Nov 29, 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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Invitae
Accession: SCV000931696.4
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 45 of the ACADM protein (p.Gln45Arg). … (more)
This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 45 of the ACADM protein (p.Gln45Arg). This variant is present in population databases (rs757434857, gnomAD 0.006%). This missense change has been observed in individual(s) with MCAD deficiency (PMID: 18241067, 20434380, 22796001; Invitae). 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: 281077). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ACADM protein function. Experimental studies have shown that this missense change affects ACADM function (PMID: 26947917). For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Mar 17, 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: SCV003922432.1
First in ClinVar: May 13, 2023 Last updated: May 13, 2023 |
Comment:
Variant summary: ACADM c.134A>G (p.Gln45Arg) results in a conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase, N-terminal domain (IPR013786) of the encoded protein sequence. … (more)
Variant summary: ACADM c.134A>G (p.Gln45Arg) results in a conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase, N-terminal domain (IPR013786) 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 1.6e-05 in 251266 control chromosomes (gnomAD). c.134A>G has been reported in the literature in the compound heterozygous state in individuals affected with Medium Chain Acyl-CoA Dehydrogenase Deficiency (e.g. Nichols_2008, Purevsuren_2009, Rucklova_2021). These data indicate that the variant may be associated with disease. A publication reporting experimental evidence evaluating an impact on protein function found that the variant resulted in reduced protein expression, which was prone to misfolding and/or aggregation, and that the variant had 11% of normal activity (Hara_2016). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic, likely pathogenic, and VUS. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Likely pathogenic
(Mar 21, 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:
unknown
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Baylor Genetics
Accession: SCV004217278.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Uncertain significance
(Jun 27, 2017)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Older claim that does not account for recent evidence
Source: ClinGen
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Medium-chain acyl-coenzyme A dehydrogenase deficiency
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000792455.1
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
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Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
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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Impact of Newborn Screening and Early Dietary Management on Clinical Outcome of Patients with Long Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency and Medium Chain Acyl-CoA Dehydrogenase Deficiency-A Retrospective Nationwide Study. | Rücklová K | Nutrients | 2021 | PMID: 34578803 |
Genotype and residual enzyme activity in medium-chain acyl-CoA dehydrogenase (MCAD) deficiency: Are predictions possible? | Tucci S | Journal of inherited metabolic disease | 2021 | PMID: 33580884 |
Variants of uncertain significance in newborn screening disorders: implications for large-scale genomic sequencing. | Narravula A | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 27308838 |
Significance of ACADM mutations identified through newborn screening of MCAD deficiency in Japan. | Hara K | Molecular genetics and metabolism | 2016 | PMID: 26947917 |
Clinical and molecular aspects of Japanese children with medium chain acyl-CoA dehydrogenase deficiency. | Purevsuren J | Molecular genetics and metabolism | 2012 | PMID: 22796001 |
Allelic diversity in MCAD deficiency: the biochemical classification of 54 variants identified during 5 years of ACADM sequencing. | Smith EH | Molecular genetics and metabolism | 2010 | PMID: 20434380 |
Lack of genotype-phenotype correlations and outcome in MCAD deficiency diagnosed by newborn screening in New York State. | Arnold GL | Molecular genetics and metabolism | 2010 | PMID: 20036593 |
A novel molecular aspect of Japanese patients with medium-chain acyl-CoA dehydrogenase deficiency (MCADD): c.449-452delCTGA is a common mutation in Japanese patients with MCADD. | Purevsuren J | Molecular genetics and metabolism | 2009 | PMID: 19064330 |
Novel mutations causing medium chain acyl-CoA dehydrogenase deficiency: under-representation of the common c.985 A > G mutation in the New York state population. | Nichols MJ | American journal of medical genetics. Part A | 2008 | PMID: 18241067 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ACADM | - | - | - | - |
Text-mined citations for rs757434857 ...
HelpRecord last updated Feb 20, 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.