ClinVar Genomic variation as it relates to human health
NM_000159.4(GCDH):c.281G>A (p.Arg94Gln)
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.281G>A (p.Arg94Gln)
Variation ID: 418224 Accession: VCV000418224.20
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 19p13.13 19: 12892125 (GRCh38) [ NCBI UCSC ] 19: 13002939 (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 Apr 27, 2017 Feb 14, 2024 Nov 18, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000159.4:c.281G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000150.1:p.Arg94Gln missense NM_013976.5:c.281G>A NP_039663.1:p.Arg94Gln missense NR_102317.1:n.697G>A non-coding transcript variant NC_000019.10:g.12892125G>A NC_000019.9:g.13002939G>A NG_009292.1:g.5966G>A NG_013087.1:g.79C>T LRG_825:g.79C>T - Protein change
- R94Q
- Other names
- -
- Canonical SPDI
- NC_000019.10:12892124: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.
-
0.00020 (A)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Exome Aggregation Consortium (ExAC) 0.00013
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
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. |
---|---|---|---|---|
Likely pathogenic (1) |
criteria provided, single submitter
|
Aug 26, 2016 | RCV000485466.1 | |
Pathogenic/Likely pathogenic (10) |
criteria provided, multiple submitters, no conflicts
|
Nov 18, 2023 | RCV000675080.21 |
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. |
|
---|---|---|---|---|---|
Likely pathogenic
(Aug 26, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000565028.4
First in ClinVar: Apr 27, 2017 Last updated: Apr 27, 2017 |
Comment:
The R94Q (c.281 G>A) variant in the GCDH gene has previously been reported in two siblings believed to have glutaric aciduria type I (GA1) who … (more)
The R94Q (c.281 G>A) variant in the GCDH gene has previously been reported in two siblings believed to have glutaric aciduria type I (GA1) who were low glutaric acid excretors and were compound heterozygous for R94Q (c.281 G>A) and another missense variant in the GCDH gene (Gupta et al. 2015). The R94Q (c.281 G>A) variant has also been seen at GeneDx in a patient sent for analysis of the GCDH gene after abnormal newborn screening results who also harbored the R402W pathogenic variant on the opposite GCDH allele (in trans). The R94Q (c.281 G>A) variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The R94Q variant is a semi-conservative amino acid substitution, which occurs at a position that is highly conserved. In silico analysis predicts that R94Q is probably damaging to the protein structure/function. Furthermore, several in-silico splice prediction models predict that the c.281 G>A nucleotide substitution, responsible for R94Q, creates a cryptic acceptor site which may supplant the natural acceptor site and lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. In summary, we interpret R94Q (c.281 G>A) to be likely pathogenic; however, the possibility that it is benign cannot be excluded. (less)
|
|
Pathogenic
(Nov 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Glutaric aciduria, type 1
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
inherited
|
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
Accession: SCV001478370.1
First in ClinVar: Feb 07, 2021 Last updated: Feb 07, 2021 |
Number of individuals with the variant: 2
Family history: yes
Sex: female
|
|
Pathogenic
(Jun 24, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Glutaric aciduria, type 1
(Autosomal recessive inheritance)
Affected status: no
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002768946.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as pathogenic. The following criteria are met: 0102 - Loss of function is a known … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as pathogenic. The following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with glutaricaciduria type I (GA-I, MIM#231670). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (31 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (2 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated Acyl-CoA dehydrogenase, N-terminal domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. The alternative amino acid change to leucine, p.(Arg94Leu) has been reported as likely pathogenic (3x) in ClinVar, however, it has not been used as supporting evidence as the change to leucine has a much larger Grantham score. In addition, p.(Arg94Trp) has been reported as a VUS in ClinVar. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in 8 individuals, including three unrelated families with GA-I (low excreter biochemical phenotype) in both compound heterozygous and homozygous state (ClinVar, PMIDs: 25762492, 31302874, 33728242, 33138774) (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Experimental studies have shown a significantly reduced Kcat of GCDH to 2% to 3% of wild type GCDH (PMID: 11024031). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
|
|
Likely pathogenic
(May 18, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Glutaric aciduria, type 1
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002811884.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
Pathogenic
(Mar 15, 2023)
|
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: SCV003922545.1
First in ClinVar: May 13, 2023 Last updated: May 13, 2023 |
Comment:
Variant summary: GCDH c.281G>A (p.Arg94Gln) 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.281G>A (p.Arg94Gln) results in a conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase, N-terminal domain (IPR013786) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 251464 control chromosomes (gnomAD). This frequency is not higher than estimated for a pathogenic variant in GCDH causing Glutaric Acidemia Type 1 (0.00012 vs 0.0035), allowing no conclusion about variant significance. c.281G>A has been reported in the literature in individuals affected with Glutaric Acidemia Type 1 (Gupta_2015, Foran_2021, Healy_2022), including two siblings. These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function indicating about 2% residual activity with glutaryl- CoA as substrate (Dwyer_2001). Another variant affecting the same amino acid (c.281G>T, p.Arg94Leu) has also been associated with GA1, suggesting an important role for this amino acid. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified it as pathogenic (n=3), likely pathogenic (n= 4) and VUS (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Glutaric aciduria, type 1
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004048470.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
The missense variant c.281G>A (p.Arg94Gln) in GCDH gene has been observed in combination with another GCDH variant in individual(s) with glutaric acidemia (Gupta N et.al.,2015). … (more)
The missense variant c.281G>A (p.Arg94Gln) in GCDH gene has been observed in combination with another GCDH variant in individual(s) with glutaric acidemia (Gupta N et.al.,2015). This variant has been reported to affect GCDH protein function (Dwyer TM et.al.,2001). This variant has been reported to the ClinVar database as Pathogenic. The p.Arg94Gln variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.01233% is reported in gnomAD. The amino acid Arg at position 94 is changed to a Gln changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Arg94Gln in GCDH is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Diarrhea (present) , Vomiting (present) , Confusion (present) , Irritability (present) , Intellectual disability (present) , Encephalopathy (present)
|
|
Likely pathogenic
(Oct 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Glutaric aciduria, type 1
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004198749.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
Likely pathogenic
(Mar 28, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Glutaric aciduria, type 1
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003832943.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
|
Pathogenic
(Nov 18, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Glutaric aciduria, type 1
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000964927.6
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 94 of the GCDH protein (p.Arg94Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 94 of the GCDH protein (p.Arg94Gln). This variant is present in population databases (rs566417795, gnomAD 0.1%). This missense change has been observed in individual(s) with glutaric acidemia (PMID: 25762492; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 418224). 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 with a negative predictive value of 80%. Experimental studies have shown that this missense change affects GCDH function (PMID: 11024031). This variant disrupts the p.Arg94 amino acid residue in GCDH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9600243). 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)
|
|
Uncertain significance
(Aug 18, 2017)
|
no assertion criteria provided
Method: clinical testing
|
Glutaric aciduria, type 1
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000800580.2
First in ClinVar: Aug 05, 2018 Last updated: Dec 23, 2019 |
|
|
Likely pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Glutaric acidemia type 1
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001454368.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
|
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 |
---|---|---|---|---|
Glutaric aciduria type 1: Diagnosis, clinical features and long-term outcome in a large cohort of 34 Irish patients. | Healy L | JIMD reports | 2022 | PMID: 35822093 |
Low excretor glutaric aciduria type 1 of insidious onset with dystonia and atypical clinical features, a diagnostic dilemma. | Foran J | JIMD reports | 2020 | PMID: 33728242 |
NGS-based expanded carrier screening for genetic disorders in North Indian population reveals unexpected results - a pilot study. | Singh K | BMC medical genetics | 2020 | PMID: 33138774 |
Is Expanded Newborn Screening Adequate to Detect Indian Biochemical Low Excretor Phenotype Patients of Glutaric Aciduria Type I? | Shaik M | Indian journal of pediatrics | 2019 | PMID: 31302874 |
Glutaric Acidemia Type 1-Clinico-Molecular Profile and Novel Mutations in GCDH Gene in Indian Patients. | Gupta N | JIMD reports | 2015 | PMID: 25762492 |
The function of Arg-94 in the oxidation and decarboxylation of glutaryl-CoA by human glutaryl-CoA dehydrogenase. | Dwyer TM | The Journal of biological chemistry | 2001 | PMID: 11024031 |
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 rs566417795 ...
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.