ClinVar Genomic variation as it relates to human health
NM_000159.4(GCDH):c.832C>T (p.Pro278Ser)
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.
Pathogenic(2); Likely pathogenic(1); Uncertain significance(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000159.4(GCDH):c.832C>T (p.Pro278Ser)
Variation ID: 643053 Accession: VCV000643053.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.13 19: 12896401 (GRCh38) [ NCBI UCSC ] 19: 13007215 (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 Aug 14, 2019 Jun 17, 2024 Feb 16, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000159.4:c.832C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000150.1:p.Pro278Ser missense NM_013976.5:c.832C>T NP_039663.1:p.Pro278Ser missense NR_102316.1:n.995C>T non-coding transcript variant NR_102317.1:n.1213C>T non-coding transcript variant NC_000019.10:g.12896401C>T NC_000019.9:g.13007215C>T NG_009292.1:g.10242C>T - Protein change
- P278S
- Other names
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- Canonical SPDI
- NC_000019.10:12896400: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.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Trans-Omics for Precision Medicine (TOPMed) 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
- Links
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 |
678 | 902 |
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
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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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Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
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Feb 16, 2024 | RCV000796665.13 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 1, 2023 | RCV003424341.6 |
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
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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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Likely pathogenic
(Oct 15, 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: SCV002600514.1
First in ClinVar: Nov 19, 2022 Last updated: Nov 19, 2022 |
Comment:
Variant summary: GCDH c.832C>T (p.Pro278Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: GCDH c.832C>T (p.Pro278Ser) results in a non-conservative amino acid change in 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 4e-06 in 249044 control chromosomes. c.832C>T has been reported in the literature as a presumed compound heterozygous genotype in at-least two individuals affected with low excretor subtype of Glutaric Acidemia Type 1 who have been subsequently cited by others (example, Schwartz_1998, Zschocke_2000, Christensen_2004, Schmiesing_2017). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (example, Schmiesing_2017). The most pronounced variant effect results in a moderate decrease in GCDH protein stability (10-26%) with no observed impact on GCDH protein expression, no effect on GCDH homo oligomerization, no effect on interaction with electron transfer flavoprotein subunit beta (ETFB) or dihydrolipoamide S-succinyltransferase (DLST). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 (Pathogenic/Likely pathogenic, n=2; VUS, n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Uncertain significance
(Nov 03, 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:
unknown
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Myriad Genetics, Inc.
Accession: SCV002060115.2
First in ClinVar: Jan 15, 2022 Last updated: Dec 24, 2022 |
Comment:
NM_000159.2(GCDH):c.832C>T(P278S) is a missense variant classified as a variant of uncertain significance in the context of glutaric acidemia, GCDH-related. P278S has been observed in cases … (more)
NM_000159.2(GCDH):c.832C>T(P278S) is a missense variant classified as a variant of uncertain significance in the context of glutaric acidemia, GCDH-related. P278S has been observed in cases with relevant disease (PMID: 15505393, 29665094). Functional assessments of this variant are available in the literature (PMID: 28062662). P278S has been observed in population frequency databases (gnomAD: NFE 0.001%). In summary, there is insufficient evidence to classify NM_000159.2(GCDH):c.832C>T(P278S) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. (less)
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Pathogenic
(Sep 15, 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: SCV000936187.4
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 278 of the GCDH protein (p.Pro278Ser). … (more)
This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 278 of the GCDH protein (p.Pro278Ser). This variant is present in population databases (rs751742575, gnomAD 0.0009%). This missense change has been observed in individual(s) with glutaric aciduria type I (PMID: 9600243, 15505393, 29665094). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro278 amino acid residue in GCDH. Other variant(s) that disrupt this residue have been observed in individuals with GCDH-related conditions (PMID: 9600243, 15505393, 22728054), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change does not substantially affect GCDH function (PMID: 28062662). 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. ClinVar contains an entry for this variant (Variation ID: 643053). (less)
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Uncertain significance
(Jan 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004137934.6
First in ClinVar: Nov 20, 2023 Last updated: Jun 17, 2024 |
Comment:
GCDH: PM2
Number of individuals with the variant: 1
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Pathogenic
(Feb 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: SCV004199212.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Likely pathogenic
(Jul 06, 2021)
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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: SCV002086979.1
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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Newborn screening: A disease-changing intervention for glutaric aciduria type 1. | Boy N | Annals of neurology | 2018 | PMID: 29665094 |
Genotype-phenotype correlation in 18 Egyptian patients with glutaric acidemia type I. | Mosaeilhy A | Metabolic brain disease | 2017 | PMID: 28389991 |
Disease-causing mutations affecting surface residues of mitochondrial glutaryl-CoA dehydrogenase impair stability, heteromeric complex formation and mitochondria architecture. | Schmiesing J | Human molecular genetics | 2017 | PMID: 28062662 |
Glutaric acidemia type 1: outcomes before and after expanded newborn screening. | Viau K | Molecular genetics and metabolism | 2012 | PMID: 22728054 |
Correlation of genotype and phenotype in glutaryl-CoA dehydrogenase deficiency. | Christensen E | Journal of inherited metabolic disease | 2004 | PMID: 15505393 |
Mutation analysis in glutaric aciduria type I. | Zschocke J | Journal of medical genetics | 2000 | PMID: 10699052 |
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 rs751742575 ...
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.