The ACADS c.1095G>T (p.Gln365His) missense variant has been reported in two studies in which it is found in a compound heterozygous state with another missense variant in two probands with short-chain acyl-coA dehydrogenase (SCAD) deficiency (Seidel et al. 2003; Pedersen et al. 2008). The p.Gln365His variant was absent from 100 control alleles and is reported at a frequency of 0.000128 in the African population of the Genome Aggregation Database. Functional studies in vitro revealed that the p.Gln365His variant was found to translate and import into mitochondria efficiently but had a decreased ability to form the mature tetrameric enzyme leading to misfolding, and a severe increased tendency to form aggregates especially at an elevated temperature (Seidel et al. 2003; Pedersen et al. 2008). Based on the evidence, the p.Gln365His variant is classified as likely pathogenic for short-chain acyl-coA dehydrogenase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
ClinVar Genomic variation as it relates to human health
NM_000017.4(ACADS):c.1095G>T (p.Gln365His)
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.
(6)
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
6
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000017.4(ACADS):c.1095G>T (p.Gln365His)
Variation ID: 203560 Accession: VCV000203560.21
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q24.31 12: 120739304 (GRCh38) [ NCBI UCSC ] 12: 121177107 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Jan 19, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000017.4:c.1095G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000008.1:p.Gln365His missense NM_001302554.2:c.1083G>T NP_001289483.1:p.Gln361His missense NC_000012.12:g.120739304G>T NC_000012.11:g.121177107G>T NG_007991.1:g.18537G>T - Protein change
- Q365H, Q361H
- Other names
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p.Q365H:CAG>CAT
- Canonical SPDI
- NC_000012.12:120739303:G:T
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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) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00003
The Genome Aggregation Database (gnomAD) 0.00006
Trans-Omics for Precision Medicine (TOPMed) 0.00006
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015
- 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. |
|||
| ACADS | - | - |
GRCh38 GRCh37 |
442 | 461 | |
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 (1) |
criteria provided, single submitter
|
Apr 7, 2022 | RCV000185694.7 | |
| Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Jan 19, 2024 | RCV000411694.20 |
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. |
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|---|---|---|---|---|---|
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Likely pathogenic
(Jan 10, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Deficiency of butyryl-CoA dehydrogenase
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000914567.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The ACADS c.1095G>T (p.Gln365His) missense variant has been reported in two studies in which it is found in a compound heterozygous state with another missense … (more)
The ACADS c.1095G>T (p.Gln365His) missense variant has been reported in two studies in which it is found in a compound heterozygous state with another missense variant in two probands with short-chain acyl-coA dehydrogenase (SCAD) deficiency (Seidel et al. 2003; Pedersen et al. 2008). The p.Gln365His variant was absent from 100 control alleles and is reported at a frequency of 0.000128 in the African population of the Genome Aggregation Database. Functional studies in vitro revealed that the p.Gln365His variant was found to translate and import into mitochondria efficiently but had a decreased ability to form the mature tetrameric enzyme leading to misfolding, and a severe increased tendency to form aggregates especially at an elevated temperature (Seidel et al. 2003; Pedersen et al. 2008). Based on the evidence, the p.Gln365His variant is classified as likely pathogenic for short-chain acyl-coA dehydrogenase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
|
|
|
Likely pathogenic
(Nov 07, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Deficiency of butyryl-CoA dehydrogenase
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV002033257.1
First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
|
|
|
Pathogenic
(Apr 07, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000238615.15
First in ClinVar: Jul 18, 2015 Last updated: Mar 04, 2023 |
Comment:
Functional analysis of Q365H found that it is associated with reduced tetramer formation, increased aggregation tendency, and increased chaperone retention compared to wild-type, similar to … (more)
Functional analysis of Q365H found that it is associated with reduced tetramer formation, increased aggregation tendency, and increased chaperone retention compared to wild-type, similar to other pathogenic variants in the ACADS gene (Seidel et al., 2003; Pedersen et al., 2008); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12872838, 18523805, 31813752, 23798014, 22241096, 18951053, 14506246) (less)
|
|
|
Pathogenic
(Mar 29, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Deficiency of butyryl-CoA dehydrogenase
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003808383.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
|
|
Likely pathogenic
(Jan 19, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Deficiency of butyryl-CoA dehydrogenase
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000952058.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 365 of the ACADS protein (p.Gln365His). … (more)
This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 365 of the ACADS protein (p.Gln365His). This variant is present in population databases (rs368469075, gnomAD 0.01%). This missense change has been observed in individuals with short-chain acyl-coenzyme A dehydrogenase deficiency (PMID: 12872838, 31813752; Invitae). This variant is also known as Gln341His. ClinVar contains an entry for this variant (Variation ID: 203560). 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 ACADS protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects ACADS function (PMID: 14506246). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
|
|
|
Likely pathogenic
(Jul 21, 2016)
|
no assertion criteria provided
Method: clinical testing
|
Deficiency of butyryl-CoA dehydrogenase
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000486661.2
First in ClinVar: Jan 07, 2017 Last updated: Dec 23, 2019 |
|
Comment:
Comment:
Functional analysis of Q365H found that it is associated with reduced tetramer formation, increased aggregation tendency, and increased chaperone retention compared to wild-type, similar to other pathogenic variants in the ACADS gene (Seidel et al., 2003; Pedersen et al., 2008); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12872838, 18523805, 31813752, 23798014, 22241096, 18951053, 14506246)
Comment:
This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 365 of the ACADS protein (p.Gln365His). This variant is present in population databases (rs368469075, gnomAD 0.01%). This missense change has been observed in individuals with short-chain acyl-coenzyme A dehydrogenase deficiency (PMID: 12872838, 31813752; Invitae). This variant is also known as Gln341His. ClinVar contains an entry for this variant (Variation ID: 203560). 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 ACADS protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects ACADS function (PMID: 14506246). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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:
The ACADS c.1095G>T (p.Gln365His) missense variant has been reported in two studies in which it is found in a compound heterozygous state with another missense variant in two probands with short-chain acyl-coA dehydrogenase (SCAD) deficiency (Seidel et al. 2003; Pedersen et al. 2008). The p.Gln365His variant was absent from 100 control alleles and is reported at a frequency of 0.000128 in the African population of the Genome Aggregation Database. Functional studies in vitro revealed that the p.Gln365His variant was found to translate and import into mitochondria efficiently but had a decreased ability to form the mature tetrameric enzyme leading to misfolding, and a severe increased tendency to form aggregates especially at an elevated temperature (Seidel et al. 2003; Pedersen et al. 2008). Based on the evidence, the p.Gln365His variant is classified as likely pathogenic for short-chain acyl-coA dehydrogenase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Comment:
Functional analysis of Q365H found that it is associated with reduced tetramer formation, increased aggregation tendency, and increased chaperone retention compared to wild-type, similar to other pathogenic variants in the ACADS gene (Seidel et al., 2003; Pedersen et al., 2008); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12872838, 18523805, 31813752, 23798014, 22241096, 18951053, 14506246)
Comment:
This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 365 of the ACADS protein (p.Gln365His). This variant is present in population databases (rs368469075, gnomAD 0.01%). This missense change has been observed in individuals with short-chain acyl-coenzyme A dehydrogenase deficiency (PMID: 12872838, 31813752; Invitae). This variant is also known as Gln341His. ClinVar contains an entry for this variant (Variation ID: 203560). 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 ACADS protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects ACADS function (PMID: 14506246). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Increased parental anxiety and a benign clinical course: Infants identified with short-chain acyl-CoA dehydrogenase deficiency and isobutyryl-CoA dehydrogenase deficiency through newborn screening in Georgia. | Sadat R | Molecular genetics and metabolism | 2020 | PMID: 31813752 |
| Neuropsychological outcomes in fatty acid oxidation disorders: 85 cases detected by newborn screening. | Waisbren SE | Developmental disabilities research reviews | 2013 | PMID: 23798014 |
| Follow-up of patients with short-chain acyl-CoA dehydrogenase and isobutyryl-CoA dehydrogenase deficiencies identified through newborn screening: one center's experience. | Pena L | Genetics in medicine : official journal of the American College of Medical Genetics | 2012 | PMID: 22241096 |
| Clinical outcomes of infants with short-chain acyl-coenzyme A dehydrogenase deficiency (SCADD) detected by newborn screening. | Jethva R | Molecular genetics and metabolism | 2008 | PMID: 18951053 |
| The ACADS gene variation spectrum in 114 patients with short-chain acyl-CoA dehydrogenase (SCAD) deficiency is dominated by missense variations leading to protein misfolding at the cellular level. | Pedersen CB | Human genetics | 2008 | PMID: 18523805 |
| Misfolding, degradation, and aggregation of variant proteins. The molecular pathogenesis of short chain acyl-CoA dehydrogenase (SCAD) deficiency. | Pedersen CB | The Journal of biological chemistry | 2003 | PMID: 14506246 |
| Recurrent vomiting and ethylmalonic aciduria associated with rare mutations of the short-chain acyl-CoA dehydrogenase gene. | Seidel J | Journal of inherited metabolic disease | 2003 | PMID: 12872838 |
Text-mined citations for rs368469075 ...
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.