Variant summary: GCDH c.442G>A (p.Val148Ile) 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 was absent in 251470 control chromosomes (gnomAD). c.442G>A has been reported in the literature in multiple bi-allelic individuals affected with Glutaric Acidemia Type 1 (examples: Schwartz_1998, Kolker_2006, Christensen_2004, and Wang_2014). These data indicate that the variant is very likely to be associated with disease. Multiple publications have reported experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (examples: Schwartz_1998, Kolker_2006, Christensen_2004). The following publications have been ascertained in the context of this evaluation (PMID: 9600243, 16641220, 15505393, 24332224). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000159.4(GCDH):c.442G>A (p.Val148Ile)
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.
(4)
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/Likely pathogenic
4
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000159.4(GCDH):c.442G>A (p.Val148Ile)
Variation ID: 2138244 Accession: VCV002138244.5
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.13 19: 12893590 (GRCh38) [ NCBI UCSC ] 19: 13004404 (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 Feb 8, 2023 Oct 13, 2024 Dec 31, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000159.4:c.442G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000150.1:p.Val148Ile missense NM_000159.3:c.442G>A NM_013976.5:c.442G>A NP_039663.1:p.Val148Ile missense NR_102316.1:n.605G>A non-coding transcript variant NR_102317.1:n.858G>A non-coding transcript variant NC_000019.10:g.12893590G>A NC_000019.9:g.13004404G>A NG_009292.1:g.7431G>A - Protein change
- V148I
- Other names
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- Canonical SPDI
- NC_000019.10:12893589: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
Help
The frequency of the allele represented by this VCV record.
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- 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 | ||
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| 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. |
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| GCDH | - | - |
GRCh38 GRCh37 |
685 | 911 | |
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/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Dec 31, 2023 | RCV003050529.6 |
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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Pathogenic
(Aug 25, 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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004039399.1
First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
Comment:
Variant summary: GCDH c.442G>A (p.Val148Ile) 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.442G>A (p.Val148Ile) 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 was absent in 251470 control chromosomes (gnomAD). c.442G>A has been reported in the literature in multiple bi-allelic individuals affected with Glutaric Acidemia Type 1 (examples: Schwartz_1998, Kolker_2006, Christensen_2004, and Wang_2014). These data indicate that the variant is very likely to be associated with disease. Multiple publications have reported experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (examples: Schwartz_1998, Kolker_2006, Christensen_2004). The following publications have been ascertained in the context of this evaluation (PMID: 9600243, 16641220, 15505393, 24332224). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
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Likely pathogenic
(Oct 13, 2023)
|
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: SCV004191001.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Dec 31, 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
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003443120.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 148 of the GCDH protein (p.Val148Ile). … (more)
This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 148 of the GCDH protein (p.Val148Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with glutaric aciduria type I (PMID: 9600243, 24332224). ClinVar contains an entry for this variant (Variation ID: 2138244). 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%. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Aug 07, 2024)
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no assertion criteria provided
Method: clinical testing
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Glutaric aciduria, type 1
Affected status: yes
Allele origin:
paternal
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Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals
Accession: SCV005367967.1
First in ClinVar: Oct 13, 2024 Last updated: Oct 13, 2024 |
|
Comment:
Comment:
This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 148 of the GCDH protein (p.Val148Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with glutaric aciduria type I (PMID: 9600243, 24332224). ClinVar contains an entry for this variant (Variation ID: 2138244). 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%. For these reasons, this variant has been classified as Pathogenic.
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:
Variant summary: GCDH c.442G>A (p.Val148Ile) 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 was absent in 251470 control chromosomes (gnomAD). c.442G>A has been reported in the literature in multiple bi-allelic individuals affected with Glutaric Acidemia Type 1 (examples: Schwartz_1998, Kolker_2006, Christensen_2004, and Wang_2014). These data indicate that the variant is very likely to be associated with disease. Multiple publications have reported experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (examples: Schwartz_1998, Kolker_2006, Christensen_2004). The following publications have been ascertained in the context of this evaluation (PMID: 9600243, 16641220, 15505393, 24332224). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 148 of the GCDH protein (p.Val148Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with glutaric aciduria type I (PMID: 9600243, 24332224). ClinVar contains an entry for this variant (Variation ID: 2138244). 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%. For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Clinical and mutational spectra of 23 Chinese patients with glutaric aciduria type 1. | Wang Q | Brain & development | 2014 | PMID: 24332224 |
| Natural history, outcome, and treatment efficacy in children and adults with glutaryl-CoA dehydrogenase deficiency. | Kölker S | Pediatric research | 2006 | PMID: 16641220 |
| Correlation of genotype and phenotype in glutaryl-CoA dehydrogenase deficiency. | Christensen E | Journal of inherited metabolic disease | 2004 | PMID: 15505393 |
| 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 this variant ...
HelpRecord last updated Oct 13, 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.