Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 18683078, 27672653, 15505393, 29419857, 29961769, 30298489, 32508882, 32005694, 35231114, 35095998, 34344405, 11058907)
ClinVar Genomic variation as it relates to human health
NM_000159.4(GCDH):c.1244-2A>C
Germline
Classification
Help
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.
(11)
Help
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.
Pathogenic
11
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000159.4(GCDH):c.1244-2A>C
Variation ID: 193976 Accession: VCV000193976.25
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.13 19: 12899466 (GRCh38) [ NCBI UCSC ] 19: 13010280 (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 Jun 28, 2015 Nov 30, 2024 Mar 5, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000159.4:c.1244-2A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice acceptor NM_001105578.2:c.613-81T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_013976.5:c.1244-234A>C intron variant NC_000019.10:g.12899466A>C NC_000019.9:g.13010280A>C NG_009292.1:g.13307A>C NG_033049.1:g.24807T>G NG_087357.1:g.235A>C - Protein change
- -
- Other names
- -
- Canonical SPDI
- NC_000019.10:12899465:A:C
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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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0.00020 (C)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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The Genome Aggregation Database (gnomAD) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00006
Exome Aggregation Consortium (ExAC) 0.00007
The Genome Aggregation Database (gnomAD), exomes 0.00009
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
- Links
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 |
686 | 913 | |
| LOC126862860 | - | - | - | GRCh38 | - | 73 |
| SYCE2 | - | - |
GRCh38 GRCh37 |
8 | 98 | |
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 (9) |
criteria provided, multiple submitters, no conflicts
|
Mar 5, 2024 | RCV000174223.24 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Apr 14, 2023 | RCV000521145.6 |
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. |
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|---|---|---|---|---|---|
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Pathogenic
(Sep 10, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000225488.5
First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Zygosity: Homozygote
Sex: mixed
|
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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: SCV000893505.2
First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022 |
|
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Pathogenic
(Apr 14, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000617681.3
First in ClinVar: Dec 19, 2017 Last updated: Apr 23, 2023 |
Comment:
Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; … (more)
Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 18683078, 27672653, 15505393, 29419857, 29961769, 30298489, 32508882, 32005694, 35231114, 35095998, 34344405, 11058907) (less)
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Pathogenic
(Sep 17, 2021)
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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
|
Revvity Omics, Revvity
Accession: SCV002024221.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Dec 13, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Glutaric aciduria, type 1
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000940791.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change affects an acceptor splice site in intron 11 of the GCDH gene. While this variant is not anticipated to result in nonsense … (more)
This sequence change affects an acceptor splice site in intron 11 of the GCDH gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is present in population databases (rs199999619, gnomAD 0.1%). Disruption of this splice site has been observed in individual(s) with glutaric aciduria, type I (PMID: 11058907, 15505393, 25256449, 27672653). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as IVS10-2A>C. ClinVar contains an entry for this variant (Variation ID: 193976). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 05, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Glutaric aciduria, type 1
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004198742.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Pathogenic
(Jun 25, 2016)
|
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: SCV000695715.1
First in ClinVar: Jun 28, 2015 Last updated: Jun 28, 2015 |
Comment:
Variant summary: The GCDH c.1244-2A>C variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. … (more)
Variant summary: The GCDH c.1244-2A>C variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 5/5 splicing algorithms predict this variant to abolish the splice acceptor site. This variant was found in 10/121612 control chromosomes at a frequency of 0.0000822, which does not exceed the estimated maximal expected allele frequency of a pathogenic GCDH variant (0.0035355).However, the variant was identified in multiple GA-1 patients in compound heterozygous or homozygous state and was shown to segregate with disease in at least one family. In addition, one clinical diagnostic laboratory classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
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Pathogenic
(Oct 01, 2021)
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criteria provided, single submitter
Method: clinical testing
|
Glutaric aciduria, type 1
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV002060356.2
First in ClinVar: Jan 15, 2022 Last updated: Nov 29, 2022 |
Comment:
NM_000159.2(GCDH):c.1244-2A>C is a canonical splice variant classified as pathogenic in the context of glutaric acidemia, GCDH-related. c.1244-2A>C has been observed in cases with relevant disease … (more)
NM_000159.2(GCDH):c.1244-2A>C is a canonical splice variant classified as pathogenic in the context of glutaric acidemia, GCDH-related. c.1244-2A>C has been observed in cases with relevant disease (PMID: 23104440, 11058907). Functional assessments of this variant are not available in the literature. c.1244-2A>C has been observed in population frequency databases (gnomAD: EAS 0.12%). In summary, NM_000159.2(GCDH):c.1244-2A>C is a canonical splice variant in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. (less)
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Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
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Glutaric aciduria, type 1
Affected status: yes
Allele origin:
germline
|
Juno Genomics, Hangzhou Juno Genomics, Inc
Accession: SCV005417388.1
First in ClinVar: Nov 30, 2024 Last updated: Nov 30, 2024 |
Comment:
PM2_Supporting+PVS1_Strong+PM3_VeryStrong+PP4
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Pathogenic
(Jun 07, 2017)
|
no assertion criteria provided
Method: curation
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Glutaric aciduria, type 1
Affected status: no
Allele origin:
germline
|
SingHealth Duke-NUS Institute of Precision Medicine
Accession: SCV000853109.1
First in ClinVar: Nov 25, 2018 Last updated: Nov 25, 2018 |
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Pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Glutaric acidemia type 1
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001456400.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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Comment:
Comment:
This sequence change affects an acceptor splice site in intron 11 of the GCDH gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is present in population databases (rs199999619, gnomAD 0.1%). Disruption of this splice site has been observed in individual(s) with glutaric aciduria, type I (PMID: 11058907, 15505393, 25256449, 27672653). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as IVS10-2A>C. ClinVar contains an entry for this variant (Variation ID: 193976). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant summary: The GCDH c.1244-2A>C variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 5/5 splicing algorithms predict this variant to abolish the splice acceptor site. This variant was found in 10/121612 control chromosomes at a frequency of 0.0000822, which does not exceed the estimated maximal expected allele frequency of a pathogenic GCDH variant (0.0035355).However, the variant was identified in multiple GA-1 patients in compound heterozygous or homozygous state and was shown to segregate with disease in at least one family. In addition, one clinical diagnostic laboratory classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Comment:
NM_000159.2(GCDH):c.1244-2A>C is a canonical splice variant classified as pathogenic in the context of glutaric acidemia, GCDH-related. c.1244-2A>C has been observed in cases with relevant disease (PMID: 23104440, 11058907). Functional assessments of this variant are not available in the literature. c.1244-2A>C has been observed in population frequency databases (gnomAD: EAS 0.12%). In summary, NM_000159.2(GCDH):c.1244-2A>C is a canonical splice variant in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Comment:
PM2_Supporting+PVS1_Strong+PM3_VeryStrong+PP4
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. |
Comment:
Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 18683078, 27672653, 15505393, 29419857, 29961769, 30298489, 32508882, 32005694, 35231114, 35095998, 34344405, 11058907)
Comment:
This sequence change affects an acceptor splice site in intron 11 of the GCDH gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is present in population databases (rs199999619, gnomAD 0.1%). Disruption of this splice site has been observed in individual(s) with glutaric aciduria, type I (PMID: 11058907, 15505393, 25256449, 27672653). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as IVS10-2A>C. ClinVar contains an entry for this variant (Variation ID: 193976). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant summary: The GCDH c.1244-2A>C variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 5/5 splicing algorithms predict this variant to abolish the splice acceptor site. This variant was found in 10/121612 control chromosomes at a frequency of 0.0000822, which does not exceed the estimated maximal expected allele frequency of a pathogenic GCDH variant (0.0035355).However, the variant was identified in multiple GA-1 patients in compound heterozygous or homozygous state and was shown to segregate with disease in at least one family. In addition, one clinical diagnostic laboratory classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Comment:
NM_000159.2(GCDH):c.1244-2A>C is a canonical splice variant classified as pathogenic in the context of glutaric acidemia, GCDH-related. c.1244-2A>C has been observed in cases with relevant disease (PMID: 23104440, 11058907). Functional assessments of this variant are not available in the literature. c.1244-2A>C has been observed in population frequency databases (gnomAD: EAS 0.12%). In summary, NM_000159.2(GCDH):c.1244-2A>C is a canonical splice variant in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Comment:
PM2_Supporting+PVS1_Strong+PM3_VeryStrong+PP4
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Clinical and Mutational Analysis of the GCDH Gene in Malaysian Patients with Glutaric Aciduria Type 1. | Abdul Wahab SA | BioMed research international | 2016 | PMID: 27672653 |
| Rare Late-Onset Presentation of Glutaric Aciduria Type I in a 16-Year-Old Woman with a Novel GCDH Mutation. | Fraidakis MJ | JIMD reports | 2015 | PMID: 25256449 |
| Promising outcomes in glutaric aciduria type I patients detected by newborn screening. | Lee CS | Metabolic brain disease | 2013 | PMID: 23104440 |
| Clinical and molecular investigation of 19 Japanese cases of glutaric acidemia type 1. | Mushimoto Y | Molecular genetics and metabolism | 2011 | PMID: 21176883 |
| Glutaric aciduria type I: outcome following detection by newborn screening. | Bijarnia S | Journal of inherited metabolic disease | 2008 | PMID: 18683078 |
| Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
| Correlation of genotype and phenotype in glutaryl-CoA dehydrogenase deficiency. | Christensen E | Journal of inherited metabolic disease | 2004 | PMID: 15505393 |
| Recurrent and novel mutations of GCDH gene in Chinese glutaric acidemia type I families. | Tang NL | Human mutation | 2000 | PMID: 11058907 |
| Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GCDH | - | - | - | - |
Text-mined citations for rs199999619 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 30, 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.