ClinVar Genomic variation as it relates to human health
NM_000159.4(GCDH):c.482G>A (p.Arg161Gln)
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
-
NM_000159.4(GCDH):c.482G>A (p.Arg161Gln)
Variation ID: 188789 Accession: VCV000188789.25
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 19p13.13 19: 12893630 (GRCh38) [ NCBI UCSC ] 19: 13004444 (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 Mar 29, 2015 Apr 6, 2024 Mar 17, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000159.4:c.482G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000150.1:p.Arg161Gln missense NM_013976.5:c.482G>A NP_039663.1:p.Arg161Gln missense NR_102316.1:n.645G>A non-coding transcript variant NR_102317.1:n.898G>A non-coding transcript variant NC_000019.10:g.12893630G>A NC_000019.9:g.13004444G>A NG_009292.1:g.7471G>A Q92947:p.Arg161Gln - Protein change
- R161Q
- Other names
- -
- Canonical SPDI
- NC_000019.10:12893629:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00004
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. |
|||
GCDH | - | - |
GRCh38 GRCh37 |
678 | 902 |
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 (10) |
criteria provided, multiple submitters, no conflicts
|
Mar 17, 2024 | RCV000169118.29 | |
Pathogenic (1) |
criteria provided, single submitter
|
Feb 9, 2016 | RCV000725818.4 |
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
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
(May 05, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Glutaric aciduria, type 1
Affected status: yes
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV001521163.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
|
|
Pathogenic
(Aug 04, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Glutaric aciduria, type 1
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000961335.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 161 of the GCDH protein (p.Arg161Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 161 of the GCDH protein (p.Arg161Gln). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GCDH function (PMID: 28062662). 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 GCDH protein function. ClinVar contains an entry for this variant (Variation ID: 188789). This missense change has been observed in individual(s) with glutaric aciduria type I (PMID: 9600243, 10960496, 20836999, 26593172, 28781846). This variant is present in population databases (rs777201305, gnomAD 0.006%). (less)
|
|
Pathogenic
(Feb 09, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000339588.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 3
Sex: mixed
|
|
Pathogenic
(Jun 11, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Glutaric aciduria, type 1
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV001430116.1
First in ClinVar: Aug 20, 2020 Last updated: Aug 20, 2020 |
Sex: male
Tissue: blood
|
|
Pathogenic
(May 13, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Glutaric aciduria, type 1
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002547876.1
First in ClinVar: Jul 17, 2022 Last updated: Jul 17, 2022 |
Comment:
Variant summary: GCDH c.482G>A (p.Arg161Gln) 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: GCDH c.482G>A (p.Arg161Gln) results in a conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase, N-terminal domain (IPR013786) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251394 control chromosomes. c.482G>A has been reported in the literature as homozygous and compound heterozygous genotypes in individuals affected with Glutaric Acidemia Type 1 (example, Popek_2010, Busquets_2000, Christensen_2004, Wang_2014). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Schmiesing_2017). The most pronounced variant effect results in loss of normal GCDH enzyme activity. The variant was also demonstrated to affect GCDH protein stability, protein homo-oligomerization and binding to electron transfer flavoprotein subunit -beta (ETFB) and dihydrolipoamide S-succinyltransferase (DLST), thereby impairing the formation of multimeric enzyme complexes. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
Likely pathogenic
(Apr 18, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Glutaric aciduria, type 1
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002779438.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
Pathogenic
(Aug 10, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Glutaric aciduria, type 1
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002024219.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
Pathogenic
(Mar 17, 2024)
|
criteria provided, single submitter
Method: research
|
Glutaric aciduria, type 1
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004804656.2
First in ClinVar: Mar 30, 2024 Last updated: Apr 06, 2024 |
|
|
Pathogenic
(Jun 06, 2019)
|
no assertion criteria provided
Method: clinical testing
|
Glutaric aciduria, type 1
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000220321.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 23, 2019 |
|
|
Pathogenic
(Jan 05, 2021)
|
no assertion criteria provided
Method: clinical testing
|
Glutaric acidemia type 1
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002086966.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
Glutaric aciduria, type 1
Affected status: yes
Allele origin:
germline
|
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare
Accession: SCV000537797.1
First in ClinVar: Mar 25, 2017 Last updated: Mar 25, 2017 |
|
|
click to load more click to collapse |
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 |
---|---|---|---|---|
Newborn screening: A disease-changing intervention for glutaric aciduria type 1. | Boy N | Annals of neurology | 2018 | PMID: 29665094 |
Excessive homozygosity identified by chromosomal microarray at a known GCDH mutation locus correlates with brain MRI abnormalities in an infant with glutaric aciduria. | Peer-Zada AA | Clinical case reports | 2017 | PMID: 28781846 |
Disease-causing mutations affecting surface residues of mitochondrial glutaryl-CoA dehydrogenase impair stability, heteromeric complex formation and mitochondria architecture. | Schmiesing J | Human molecular genetics | 2017 | PMID: 28062662 |
Glutaric aciduria type 1 as a cause of dystonic cerebral palsy. | Mohamed S | Saudi medical journal | 2015 | PMID: 26593172 |
Clinical and mutational spectra of 23 Chinese patients with glutaric aciduria type 1. | Wang Q | Brain & development | 2014 | PMID: 24332224 |
Two inborn errors of metabolism in a newborn: glutaric aciduria type I combined with isobutyrylglycinuria. | Popek M | Clinica chimica acta; international journal of clinical chemistry | 2010 | PMID: 20836999 |
Dynamic changes of striatal and extrastriatal abnormalities in glutaric aciduria type I. | Harting I | Brain : a journal of neurology | 2009 | PMID: 19433437 |
Cerebral 1H MR spectroscopy revealing white matter NAA decreases in glutaric aciduria type I. | Sijens PE | Molecular genetics and metabolism | 2006 | PMID: 16488172 |
Correlation of genotype and phenotype in glutaryl-CoA dehydrogenase deficiency. | Christensen E | Journal of inherited metabolic disease | 2004 | PMID: 15505393 |
Glutaryl-CoA dehydrogenase deficiency in Spain: evidence of two groups of patients, genetically, and biochemically distinct. | Busquets C | Pediatric research | 2000 | PMID: 10960496 |
The human glutaryl-CoA dehydrogenase gene: report of intronic sequences and of 13 novel mutations causing glutaric aciduria type I. | Schwartz M | Human genetics | 1998 | PMID: 9600243 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GCDH | - | - | - | - |
click to load more click to collapse |
Text-mined citations for rs777201305 ...
HelpRecord last updated Jun 10, 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.