ClinVar Genomic variation as it relates to human health
NM_001918.5(DBT):c.916T>C (p.Ser306Pro)
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_001918.5(DBT):c.916T>C (p.Ser306Pro)
Variation ID: 1342860 Accession: VCV001342860.5
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p21.2 1: 100214840 (GRCh38) [ NCBI UCSC ] 1: 100680396 (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 Mar 5, 2022 Feb 14, 2024 Oct 23, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001918.5:c.916T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001909.4:p.Ser306Pro missense NC_000001.11:g.100214840A>G NC_000001.10:g.100680396A>G NG_011852.2:g.40014T>C - Protein change
- S306P
- Other names
- GRCh37:1:100680396:A:G
- NC_000001.10:g.100680396A>G
- Canonical SPDI
- NC_000001.11:100214839:A:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- Uncertain function
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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.
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- 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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DBT | - | - |
GRCh38 GRCh37 |
806 | 819 |
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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Uncertain significance (1) |
no assertion criteria provided
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Mar 1, 2022 | RCV001840964.1 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Oct 23, 2023 | RCV002543269.6 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
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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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Pathogenic
(Oct 19, 2023)
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criteria provided, single submitter
Method: clinical testing
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Maple syrup urine disease
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004121869.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
Variant summary: DBT c.916T>C (p.Ser306Pro) results in a non-conservative amino acid change located in the catalytic domain (IPR001078) of the encoded protein sequence. Four of … (more)
Variant summary: DBT c.916T>C (p.Ser306Pro) results in a non-conservative amino acid change located in the catalytic domain (IPR001078) 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 251458 control chromosomes (gnomAD). c.916T>C has been reported in the literature in multiple compound heterozygous individuals affected with Maple Syrup Urine Disease (Strauss_2020, Billington_2022). These data indicate that the variant is very likely to be associated with disease. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated severely reduced protein level and enzyme activity in patient derived cells (Billington_2022). The following publications have been ascertained in the context of this evaluation (PMID: 31980395, 35799415). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jul 26, 2023)
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criteria provided, single submitter
Method: clinical testing
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Maple syrup urine disease type 1A
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004190855.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Oct 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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Maple syrup urine disease
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003449112.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 306 of the DBT protein (p.Ser306Pro). … (more)
This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 306 of the DBT protein (p.Ser306Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with maple syrup urine disease (PMID: 31980395; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1342860). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DBT protein function. For these reasons, this variant has been classified as Pathogenic. (less)
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Uncertain significance
(Mar 01, 2022)
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no assertion criteria provided
Method: clinical testing
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Maple syrup urine disease type 2
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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clinical biochemical genetics laboratory, stanford university
Accession: SCV002102395.1
First in ClinVar: Mar 05, 2022 Last updated: Mar 05, 2022 |
Comment:
The p.Ser306Pro variant in DBT was detected in trans with a pathogenic variant in an individual with a biochemical diagnosis of Maple Syrup Urine Disease … (more)
The p.Ser306Pro variant in DBT was detected in trans with a pathogenic variant in an individual with a biochemical diagnosis of Maple Syrup Urine Disease (MSUD). The nucleotide is weakly conserved, while the amino acid is highly conserved with moderate physicochemical difference between serine and proline. The variant is in the catalytic acyltransferase domain of the protein, and has not been seen in the large population databases. Computational predictors do not agree if the variant is deleterious or tolerable. The variant has been reported once before, in the heterozygous state as a variant of unknown significance, as an incidental finding in an individual who did not have MSUD (Park 2016). (less)
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Germline Functional Evidence
Functional
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The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
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A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
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A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Uncertain function
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clinical biochemical genetics laboratory, stanford university
Accession: SCV002102395.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Genomic and biochemical analysis of repeatedly observed variants in DBT in individuals with maple syrup urine disease of Central American ancestry. | Billington CJ Jr | American journal of medical genetics. Part A | 2022 | PMID: 35799415 |
Branched-chain α-ketoacid dehydrogenase deficiency (maple syrup urine disease): Treatment, biomarkers, and outcomes. | Strauss KA | Molecular genetics and metabolism | 2020 | PMID: 31980395 |
A Population-Based Genomic Study of Inherited Metabolic Diseases Detected Through Newborn Screening. | Park KJ | Annals of laboratory medicine | 2016 | PMID: 27578510 |
Text-mined citations for rs2100797134 ...
HelpRecord last updated Sep 29, 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.