ClinVar Genomic variation as it relates to human health
NM_000159.4(GCDH):c.1156C>T (p.Arg386Ter)
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.1156C>T (p.Arg386Ter)
Variation ID: 235616 Accession: VCV000235616.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.13 19: 12897776 (GRCh38) [ NCBI UCSC ] 19: 13008590 (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 Nov 4, 2017 Feb 14, 2024 Sep 29, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000159.4:c.1156C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000150.1:p.Arg386Ter nonsense NM_013976.5:c.1156C>T NP_039663.1:p.Arg386Ter nonsense NR_102316.1:n.1319C>T non-coding transcript variant NR_102317.1:n.1537C>T non-coding transcript variant NC_000019.10:g.12897776C>T NC_000019.9:g.13008590C>T NG_009292.1:g.11617C>T NG_033049.1:g.26497G>A - Protein change
- R386*
- Other names
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- Canonical SPDI
- NC_000019.10:12897775: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.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
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 |
682 | 908 |
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 (1) |
criteria provided, single submitter
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Oct 5, 2017 | RCV000224565.3 | |
Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
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Sep 29, 2023 | RCV000778541.18 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV002222454.2 |
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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Pathogenic
(Oct 05, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000281333.2
First in ClinVar: Jun 09, 2016 Last updated: Nov 04, 2017 |
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Pathogenic
(Sep 12, 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: SCV000914832.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The GCDH c.1156C>T (p.Arg386Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. The p.Arg386Ter variant has … (more)
The GCDH c.1156C>T (p.Arg386Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. The p.Arg386Ter variant has been reported in four studies and is found in at least four probands with glutaric acidemia including two in a homozygous state, two in a compound heterozygous state, and two in a heterozygous state without an identified second allele (Biery et al. 1996; Zschocke et al. 2000; Christensen et al. 2004; Tsai et al. 2017). Control data are unavailable for the p.Arg386Ter variant, which is reported at a frequency of 0.000011 in the Total population of the Genome Aggregation Database. Expression analysis in E. coli and fibroblasts found the p.Arg386Ter variant exhibited a greater than 95% reduction in GCD activity (Biery et al. 1996; Christensen et al. 2004). Due to the potential impact of stop-gained variants, the p.Arg386Ter 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
(Aug 06, 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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000917451.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: GCDH c.1156C>T (p.Arg386X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: GCDH c.1156C>T (p.Arg386X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 1.1e-05 in 277140 control chromosomes (gnomAD). The variant, c.1156C>T has been reported in the literature in multiple individuals affected with Glutaric Acidemia Type 1 (Biery_1996, Christensen_2004, Koker_2007). 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. The most pronounced variant effect results in <10% of normal activity (Christensen_2004). A ClinVar submission from another clinical diagnostic laboratory (evaluation after 2014) cite the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Hypomyelinating leukodystrophy 2
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
inherited
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Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
Accession: SCV002500847.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Sex: male
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Glutaric aciduria, type 1
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Lifecell International Pvt. Ltd
Accession: SCV003923327.1
First in ClinVar: May 13, 2023 Last updated: May 13, 2023 |
Comment:
A Heterozygous Nonsense variant c.1156C>T in Exon 11 of the GCDH gene that results in the amino acid substitution p.Arg386* was identified. The observed variant … (more)
A Heterozygous Nonsense variant c.1156C>T in Exon 11 of the GCDH gene that results in the amino acid substitution p.Arg386* was identified. The observed variant has a minor allele frequency of 0.00001/0.00003% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic(variant ID: 235616). This variant has been observed in many individuals affected with Glutaricaciduria, type I reported by (Kölker S et al., 2007). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines. (less)
Ethnicity/Population group: Asian
Geographic origin: India
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Pathogenic
(Sep 27, 2023)
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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: SCV004199199.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Feb 12, 2019)
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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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Revvity Omics, Revvity
Accession: SCV002024226.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Sep 29, 2023)
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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: SCV001222403.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg386*) in the GCDH gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg386*) in the GCDH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GCDH are known to be pathogenic (PMID: 10699052, 11854167, 16602100). This variant is present in population databases (rs752127949, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with glutaric aciduria type I (PMID: 8900227, 15505393, 28302372). ClinVar contains an entry for this variant (Variation ID: 235616). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Sep 16, 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: SCV001456395.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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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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Experiences during newborn screening for glutaric aciduria type 1: Diagnosis, treatment, genotype, phenotype, and outcomes. | Tsai FC | Journal of the Chinese Medical Association : JCMA | 2017 | PMID: 28302372 |
Decline of acute encephalopathic crises in children with glutaryl-CoA dehydrogenase deficiency identified by newborn screening in Germany. | Kölker S | Pediatric research | 2007 | PMID: 17622945 |
Glutaric acidemia type 1. | Hedlund GL | American journal of medical genetics. Part C, Seminars in medical genetics | 2006 | PMID: 16602100 |
Correlation of genotype and phenotype in glutaryl-CoA dehydrogenase deficiency. | Christensen E | Journal of inherited metabolic disease | 2004 | PMID: 15505393 |
Biochemical, pathologic and behavioral analysis of a mouse model of glutaric acidemia type I. | Koeller DM | Human molecular genetics | 2002 | PMID: 11854167 |
Mutation analysis in glutaric aciduria type I. | Zschocke J | Journal of medical genetics | 2000 | PMID: 10699052 |
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 |
Text-mined citations for rs752127949 ...
HelpRecord last updated Jun 23, 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.