ClinVar Genomic variation as it relates to human health
NM_000159.4(GCDH):c.1064G>A (p.Arg355His)
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.1064G>A (p.Arg355His)
Variation ID: 459947 Accession: VCV000459947.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.13 19: 12897410 (GRCh38) [ NCBI UCSC ] 19: 13008224 (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 26, 2017 Jun 17, 2024 Mar 16, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000159.4:c.1064G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000150.1:p.Arg355His missense NM_013976.5:c.1064G>A NP_039663.1:p.Arg355His missense NR_102316.1:n.1227G>A non-coding transcript variant NR_102317.1:n.1445G>A non-coding transcript variant NC_000019.10:g.12897410G>A NC_000019.9:g.13008224G>A NG_009292.1:g.11251G>A NG_033049.1:g.26863C>T - Protein change
- R355H
- Other names
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- Canonical SPDI
- NC_000019.10:12897409:G:A
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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) 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
Exome Aggregation Consortium (ExAC) 0.00003
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 | ||
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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
Help
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
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
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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 (4) |
criteria provided, multiple submitters, no conflicts
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Mar 16, 2024 | RCV000551437.10 |
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
(May 04, 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:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002547877.1
First in ClinVar: Jul 17, 2022 Last updated: Jul 17, 2022 |
Comment:
Variant summary: GCDH c.1064G>A (p.Arg355His) results in a non-conservative amino acid change located in the C-terminal domain (IPR009075) of the encoded protein sequence. Five of … (more)
Variant summary: GCDH c.1064G>A (p.Arg355His) results in a non-conservative amino acid change located in the C-terminal domain (IPR009075) of the encoded protein sequence. Five 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 250458 control chromosomes (gnomAD). c.1064G>A has been reported in the literature in several homozygous and compound heterozygous individuals affected with Glutaric Acidemia Type 1 (e.g. Schwartz_1998, Ikeda_1998, Wang_2014, Huishu_2021). These data indicate that the variant is very likely to be associated with disease. At least one publication reported undetectable GCDH activity in cultured fibroblasts isolated from a homozygous patient (Schwartz_1998). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and both of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Dec 13, 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: SCV000631929.5
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 355 of the GCDH protein (p.Arg355His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 355 of the GCDH protein (p.Arg355His). This variant is present in population databases (rs748275416, gnomAD 0.006%). This missense change has been observed in individual(s) with glutaric acidemia type I (PMID: 9600243, 9856558, 10699052, 21176883). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 459947). 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%. This variant disrupts the p.Arg355 amino acid residue in GCDH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9711871, 26071121). 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
(Mar 16, 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: SCV004191002.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Pathogenic
(Aug 31, 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: SCV002086989.1
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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Evaluation of the Clinical, Biochemical, Neurological, and Genetic Presentations of Glutaric Aciduria Type 1 in Patients From China. | E H | Frontiers in genetics | 2021 | PMID: 34306040 |
Spectrum of mutations in Glutaryl-CoA dehydrogenase gene in glutaric aciduria type I--Study from South India. | Radha Rama Devi A | Brain & development | 2016 | PMID: 26071121 |
Clinical and mutational spectra of 23 Chinese patients with glutaric aciduria type 1. | Wang Q | Brain & development | 2014 | PMID: 24332224 |
Clinical and molecular investigation of 19 Japanese cases of glutaric acidemia type 1. | Mushimoto Y | Molecular genetics and metabolism | 2011 | PMID: 21176883 |
Mutation analysis in glutaric aciduria type I. | Zschocke J | Journal of medical genetics | 2000 | PMID: 10699052 |
Novel mutations of the glutaryl-CoA dehydrogenase gene in two Japanese patients with glutaric aciduria type I. | Ikeda H | American journal of medical genetics | 1998 | PMID: 9856558 |
Glutaryl-CoA dehydrogenase mutations in glutaric acidemia (type I): review and report of thirty novel mutations. | Goodman SI | Human mutation | 1998 | PMID: 9711871 |
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 |
Text-mined citations for rs748275416 ...
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.