ClinVar Genomic variation as it relates to human health
NM_000159.4(GCDH):c.262C>T (p.Arg88Cys)
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_000159.4(GCDH):c.262C>T (p.Arg88Cys)
Variation ID: 189150 Accession: VCV000189150.22
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.13 19: 12891965 (GRCh38) [ NCBI UCSC ] 19: 13002779 (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 Mar 29, 2015 Jun 17, 2024 Mar 19, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000159.4:c.262C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000150.1:p.Arg88Cys missense NM_013976.5:c.262C>T NP_039663.1:p.Arg88Cys missense NR_102316.1:n.370C>T non-coding transcript variant NR_102317.1:n.678C>T non-coding transcript variant NC_000019.10:g.12891965C>T NC_000019.9:g.13002779C>T NG_009292.1:g.5806C>T NG_013087.1:g.239G>A LRG_825:g.239G>A Q92947:p.Arg88Cys - Protein change
- R88C
- Other names
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- Canonical SPDI
- NC_000019.10:12891964:C: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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00007
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015
Exome Aggregation Consortium (ExAC) 0.00005
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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GCDH | - | - |
GRCh38 GRCh37 |
678 | 902 |
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 (7) |
criteria provided, multiple submitters, no conflicts
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Mar 19, 2024 | RCV000169574.20 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 13, 2022 | RCV000255875.5 |
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
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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
(Apr 06, 2017)
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criteria provided, single submitter
Method: clinical testing
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Glutaric aciduria, type 1
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000695717.1
First in ClinVar: Mar 29, 2015 Last updated: Mar 29, 2015 |
Comment:
Variant summary: The GCDH c.262C>T (p.Arg88Cys) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant … (more)
Variant summary: The GCDH c.262C>T (p.Arg88Cys) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 6/121308 control chromosomes at a frequency of 0.0000495, which does not exceed the estimated maximal expected allele frequency of a pathogenic GCDH variant (0.0035355). The variant was reported in numerous affected individuals in the literature and functional studies using both expression systems as well as patient firbroblasts show the variant to have a complete loss of GCDH activity (Biery_1996, CHRISTENSEN_2004). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic. (less)
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Pathogenic
(Oct 16, 2018)
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criteria provided, single submitter
Method: clinical testing
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Glutaric aciduria, type 1
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000915818.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
Across a selection of the available literature, the GCDH c.262C>T (p.Arg88Cys) variant has been identified in ten probands with glutaric acidemia, including four who carried … (more)
Across a selection of the available literature, the GCDH c.262C>T (p.Arg88Cys) variant has been identified in ten probands with glutaric acidemia, including four who carried the variant in a homozygous state and six who carried the variant in a compound heterozygous state, and in an additional seven proband alleles (Biery et al. 1996; Schwartz et al. 1998; Busquets et al. 2000; Zschocke et al. 2000; Al-Dirbashi et al. 2011; Bhattacharjee et al. 2015; Schmiesing et al. 2017). Control data are unavailable for this variant, which is reported at a frequency of 0.000108 in the European (non-Finnish) population of the Genome Aggregation Database. Expression of wild type and p.Arg88Cys variant GCDH in E. coli revealed the p.Arg88Cys variant produced stable protein, however Western blotting found no enzyme activity (Biery et al. 1996). Expression of the p.Arg88Cys variant in HeLa cells revealed expression and degradation rates similar to wild type and normal mitochondrial localization but abnormal mitochondrial architecture, while expression in HEK293T cells revealed no negative impact on oligomer formation (Schmiesing et al. 2017). Based on the collective evidence, the p.Arg88Cys variant is classified as pathogenic for glutaric acidemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Pathogenic
(Jan 13, 2022)
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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: SCV000321704.9
First in ClinVar: Oct 09, 2016 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate this variant results in glutaryl-CoA dehydrogenase activity that is less than 1% of the activity of expressed wild-type protein (Biery et … (more)
Published functional studies demonstrate this variant results in glutaryl-CoA dehydrogenase activity that is less than 1% of the activity of expressed wild-type protein (Biery et al., 1996); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25255367, 24332224, 23395213, 25087612, 28438223, 28062662, 8900227, 10699052, 11073722, 19433437, 31536184, 33064266, 32778825) (less)
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Pathogenic
(Mar 19, 2024)
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criteria provided, single submitter
Method: clinical testing
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Glutaric aciduria, type 1
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV001521162.2
First in ClinVar: Mar 22, 2021 Last updated: Jun 17, 2024 |
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Pathogenic
(Apr 29, 2022)
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criteria provided, single submitter
Method: clinical testing
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Glutaric aciduria, type 1
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002810350.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Jan 19, 2024)
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criteria provided, single submitter
Method: clinical testing
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Glutaric aciduria, type 1
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000756251.8
First in ClinVar: May 03, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 88 of the GCDH protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 88 of the GCDH protein (p.Arg88Cys). This variant is present in population databases (rs142967670, gnomAD 0.01%). This missense change has been observed in individual(s) with glutaric aciduria type I (PMID: 8900227, 10699052, 11073722, 19433437, 23395213, 28438223). ClinVar contains an entry for this variant (Variation ID: 189150). 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 GCDH protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GCDH function (PMID: 8900227). This variant disrupts the p.Arg88 amino acid residue in GCDH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21811973, 23395213, 24332224). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Nov 14, 2018)
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no assertion criteria provided
Method: clinical testing
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Glutaric aciduria, type 1
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000221076.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 23, 2019 |
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Pathogenic
(Jul 24, 2020)
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no assertion criteria provided
Method: clinical testing
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Glutaric acidemia type 1
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002086957.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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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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Extrastriatal changes in patients with late-onset glutaric aciduria type I highlight the risk of long-term neurotoxicity. | Boy N | Orphanet journal of rare diseases | 2017 | PMID: 28438223 |
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 |
Targeted Next Generation Sequencing in Patients with Inborn Errors of Metabolism. | Yubero D | PloS one | 2016 | PMID: 27243974 |
Clinical application of whole-exome sequencing across clinical indications. | Retterer K | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 26633542 |
Development of DNA confirmatory and high-risk diagnostic testing for newborns using targeted next-generation DNA sequencing. | Bhattacharjee A | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25255367 |
Clinical and mutational spectra of 23 Chinese patients with glutaric aciduria type 1. | Wang Q | Brain & development | 2014 | PMID: 24332224 |
Glutaric aciduria type I: outcome of patients with early- versus late-diagnosis. | Couce ML | European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society | 2013 | PMID: 23395213 |
[Mutation analysis of GCDH gene in eight patients with glutaric aciduria type I]. | Chen J | Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics | 2011 | PMID: 21811973 |
Diagnosis of glutaric aciduria type 1 by measuring 3-hydroxyglutaric acid in dried urine spots by liquid chromatography tandem mass spectrometry. | Al-Dirbashi OY | Journal of inherited metabolic disease | 2011 | PMID: 20978942 |
Dynamic changes of striatal and extrastriatal abnormalities in glutaric aciduria type I. | Harting I | Brain : a journal of neurology | 2009 | PMID: 19433437 |
Correlation of genotype and phenotype in glutaryl-CoA dehydrogenase deficiency. | Christensen E | Journal of inherited metabolic disease | 2004 | PMID: 15505393 |
Mutation analysis of the GCDH gene in Italian and Portuguese patients with glutaric aciduria type I. | Busquets C | Molecular genetics and metabolism | 2000 | PMID: 11073722 |
Mutation analysis in glutaric aciduria type I. | Zschocke J | Journal of medical genetics | 2000 | PMID: 10699052 |
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 |
Gene structure and mutations of glutaryl-coenzyme A dehydrogenase: impaired association of enzyme subunits that is due to an A421V substitution causes glutaric acidemia type I in the Amish. | Biery BJ | American journal of human genetics | 1996 | PMID: 8900227 |
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Text-mined citations for rs142967670 ...
HelpRecord last updated Jun 17, 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.