ClinVar Genomic variation as it relates to human health
NM_000159.4(GCDH):c.572T>C (p.Met191Thr)
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.572T>C (p.Met191Thr)
Variation ID: 198396 Accession: VCV000198396.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.13 19: 12896058 (GRCh38) [ NCBI UCSC ] 19: 13006872 (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 Feb 20, 2024 Jan 22, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000159.4:c.572T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000150.1:p.Met191Thr missense NM_013976.5:c.572T>C NP_039663.1:p.Met191Thr missense NR_102316.1:n.735T>C non-coding transcript variant NR_102317.1:n.988T>C non-coding transcript variant NC_000019.10:g.12896058T>C NC_000019.9:g.13006872T>C NG_009292.1:g.9899T>C Q92947:p.Met191Thr - Protein change
- M191T
- Other names
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- Canonical SPDI
- NC_000019.10:12896057:T: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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Allele frequency
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The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00006
The Genome Aggregation Database (gnomAD), exomes 0.00008
Trans-Omics for Precision Medicine (TOPMed) 0.00011
The Genome Aggregation Database (gnomAD) 0.00018
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00038
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
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 |
678 | 902 |
Conditions - Germline
Condition
Help
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
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 (7) |
criteria provided, multiple submitters, no conflicts
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Jan 22, 2024 | RCV000179723.19 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Apr 20, 2015 | RCV000724678.4 |
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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Likely pathogenic
(Apr 20, 2015)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000232017.5
First in ClinVar: Jun 29, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(Apr 16, 2018)
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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: SCV000919424.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: GCDH c.572T>C (p.Met191Thr) results in a non-conservative amino acid change located in the Acyl-CoA oxidase/dehydrogenase central domain of the encoded protein sequence. Five … (more)
Variant summary: GCDH c.572T>C (p.Met191Thr) results in a non-conservative amino acid change located in the Acyl-CoA oxidase/dehydrogenase central domain 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 8.3e-05 in 277158 control chromosomes. This frequency is not higher than expected for a pathogenic variant in GCDH causing Glutaric Acidemia Type 1, allowing no conclusion about variant significance. The c.572T>C has been reported in the literature in multiple individuals affected with Glutaric Acidemia Type 1. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Oct 19, 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:
unknown
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Baylor Genetics
Accession: SCV004190993.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Apr 27, 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:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002809910.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Jun 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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Revvity Omics, Revvity
Accession: SCV004236825.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 22, 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:
germline
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Invitae
Accession: SCV000631938.7
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 191 of the GCDH protein (p.Met191Thr). … (more)
This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 191 of the GCDH protein (p.Met191Thr). This variant is present in population databases (rs149120354, gnomAD 0.02%). This missense change has been observed in individual(s) with GCDH enzymatic activity <0.5% of wild-type, findings that are highly specific for glutaric aciduria type I (PMID: 9600243). ClinVar contains an entry for this variant (Variation ID: 198396). 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
(Mar 13, 2017)
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no assertion criteria provided
Method: clinical testing
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Glutaric aciduria, type 1
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000677904.2
First in ClinVar: Jan 06, 2018 Last updated: Dec 23, 2019 |
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Pathogenic
(Sep 16, 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: SCV001456388.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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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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Glutaric Acidemia Type 1: A Case of Infantile Stroke. | Kaya Ozcora GD | JIMD reports | 2018 | PMID: 28411331 |
Use of guidelines improves the neurological outcome in glutaric aciduria type I. | Heringer J | Annals of neurology | 2010 | PMID: 21031586 |
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 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GCDH | - | - | - | - |
Text-mined citations for rs149120354 ...
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.