Variant summary: DBT c.939G>C (p.Lys313Asn) results in a non-conservative amino acid change located in the 2-oxoacid dehydrogenase acyltransferase, catalytic domain (IPR001078) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a canonical 5' splicing donor site and two predict the variant weakens the same canonical 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.2e-05 in 251402 control chromosomes (gnomAD). c.939G>C has been reported in the literature as a biallelic genotype in multiple individuals affected with Maple Syrup Urine Disease (Quental_2008, Gupta_2015, Cheema_2020, Strauss_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33083013, 26257134, 18378174, 31980395). Three ClinVar submitters have assessed the variant since 2014: one classified the variant as likely pathogenic and two as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_001918.5(DBT):c.939G>C (p.Lys313Asn)
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.
(7)
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
7
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001918.5(DBT):c.939G>C (p.Lys313Asn)
Variation ID: 94017 Accession: VCV000094017.15
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 1p21.2 1: 100214817 (GRCh38) [ NCBI UCSC ] 1: 100680373 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 11, 2016 Feb 14, 2024 Oct 4, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001918.5:c.939G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001909.4:p.Lys313Asn missense NC_000001.11:g.100214817C>G NC_000001.10:g.100680373C>G NG_011852.2:g.40037G>C NP_001909.3:p.Lys313Asn - Protein change
- K313N
- Other names
- -
- Canonical SPDI
- NC_000001.11:100214816:C:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD), exomes 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
- 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. |
|||
| DBT | - | - |
GRCh38 GRCh37 |
806 | 819 | |
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 (5) |
criteria provided, multiple submitters, no conflicts
|
Oct 4, 2023 | RCV000179839.14 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Sep 4, 2013 | RCV000790732.4 | |
| Pathogenic (1) |
criteria provided, single submitter
|
- | RCV001250158.1 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Jan 01, 2013)
|
criteria provided, single submitter
Method: research
|
Maple syrup urine disease type 1A
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital
Accession: SCV000240048.1
First in ClinVar: Mar 11, 2016 Last updated: Mar 11, 2016
Comment:
homozygous in 2 patients and hetrozygous in one
|
Number of individuals with the variant: 3
|
|
|
Likely pathogenic
(May 16, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Maple syrup urine disease type 1A
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000791370.1
First in ClinVar: Mar 11, 2016 Last updated: Mar 11, 2016 |
|
|
|
Pathogenic
(Sep 04, 2013)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000232154.5
First in ClinVar: Jun 28, 2015 Last updated: Jul 30, 2019 |
Number of individuals with the variant: 3
Sex: mixed
|
|
|
Pathogenic
(Oct 04, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Maple syrup urine disease
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004122501.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
Variant summary: DBT c.939G>C (p.Lys313Asn) results in a non-conservative amino acid change located in the 2-oxoacid dehydrogenase acyltransferase, catalytic domain (IPR001078) of the encoded protein … (more)
Variant summary: DBT c.939G>C (p.Lys313Asn) results in a non-conservative amino acid change located in the 2-oxoacid dehydrogenase acyltransferase, catalytic domain (IPR001078) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a canonical 5' splicing donor site and two predict the variant weakens the same canonical 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.2e-05 in 251402 control chromosomes (gnomAD). c.939G>C has been reported in the literature as a biallelic genotype in multiple individuals affected with Maple Syrup Urine Disease (Quental_2008, Gupta_2015, Cheema_2020, Strauss_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33083013, 26257134, 18378174, 31980395). Three ClinVar submitters have assessed the variant since 2014: one classified the variant as likely pathogenic and two as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Maple syrup urine disease type II
Affected status: yes
Allele origin:
germline
|
Centogene AG - the Rare Disease Company
Accession: SCV001424399.1
First in ClinVar: Jul 27, 2020 Last updated: Jul 27, 2020 |
|
|
|
Pathogenic
(Nov 07, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Maple syrup urine disease type 1A
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV002033190.1
First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
|
|
|
Pathogenic
(Jan 17, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Maple syrup urine disease
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001410080.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
ClinVar contains an entry for this variant (Variation ID: 94017). For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus … (more)
ClinVar contains an entry for this variant (Variation ID: 94017). For these reasons, this variant has been classified as Pathogenic. 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This missense change has been observed in individuals with maple syrup urine disease (PMID: 18378174, 26257134). This variant is present in population databases (rs398123676, gnomAD 0.01%). This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 313 of the DBT protein (p.Lys313Asn). This variant also falls at the last nucleotide of exon 7, which is part of the consensus splice site for this exon. (less)
|
Comment:
Comment:
ClinVar contains an entry for this variant (Variation ID: 94017). For these reasons, this variant has been classified as Pathogenic. 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This missense change has been observed in individuals with maple syrup urine disease (PMID: 18378174, 26257134). This variant is present in population databases (rs398123676, gnomAD 0.01%). This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 313 of the DBT protein (p.Lys313Asn). This variant also falls at the last nucleotide of exon 7, which is part of the consensus splice site for this exon.
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: DBT c.939G>C (p.Lys313Asn) results in a non-conservative amino acid change located in the 2-oxoacid dehydrogenase acyltransferase, catalytic domain (IPR001078) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a canonical 5' splicing donor site and two predict the variant weakens the same canonical 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.2e-05 in 251402 control chromosomes (gnomAD). c.939G>C has been reported in the literature as a biallelic genotype in multiple individuals affected with Maple Syrup Urine Disease (Quental_2008, Gupta_2015, Cheema_2020, Strauss_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33083013, 26257134, 18378174, 31980395). Three ClinVar submitters have assessed the variant since 2014: one classified the variant as likely pathogenic and two as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
ClinVar contains an entry for this variant (Variation ID: 94017). For these reasons, this variant has been classified as Pathogenic. 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This missense change has been observed in individuals with maple syrup urine disease (PMID: 18378174, 26257134). This variant is present in population databases (rs398123676, gnomAD 0.01%). This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 313 of the DBT protein (p.Lys313Asn). This variant also falls at the last nucleotide of exon 7, which is part of the consensus splice site for this exon.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Genomic testing in 1019 individuals from 349 Pakistani families results in high diagnostic yield and clinical utility. | Cheema H | NPJ genomic medicine | 2020 | PMID: 33083013 |
| Branched-chain α-ketoacid dehydrogenase deficiency (maple syrup urine disease): Treatment, biomarkers, and outcomes. | Strauss KA | Molecular genetics and metabolism | 2020 | PMID: 31980395 |
| Identification of mutations, genotype-phenotype correlation and prenatal diagnosis of maple syrup urine disease in Indian patients. | Gupta D | European journal of medical genetics | 2015 | PMID: 26257134 |
| Molecular and structural analyses of maple syrup urine disease and identification of a founder mutation in a Portuguese Gypsy community. | Quental S | Molecular genetics and metabolism | 2008 | PMID: 18378174 |
| 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 |
| 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=DBT | - | - | - | - |
Text-mined citations for rs398123676 ...
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 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.