NM_001918.4(DBT):c.901C>T (p.Arg301Cys) AND Maple syrup urine disease

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Oct 20, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
4 submissions [Details]
Record status:
current
Accession:
RCV000179836.13

Allele description [Variation Report for NM_001918.4(DBT):c.901C>T (p.Arg301Cys)]

NM_001918.4(DBT):c.901C>T (p.Arg301Cys)

Gene:
DBT:dihydrolipoamide branched chain transacylase E2 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
1p21.2
Genomic location:
Preferred name:
NM_001918.4(DBT):c.901C>T (p.Arg301Cys)
Other names:
p.R301C:CGT>TGT
HGVS:
  • NC_000001.11:g.100214855G>A
  • NG_011852.2:g.39999C>T
  • NM_001918.4:c.901C>T
  • NP_001909.3:p.Arg301Cys
  • NP_001909.3:p.Arg301Cys
  • NC_000001.10:g.100680411G>A
  • NM_001918.2:c.901C>T
  • NM_001918.3:c.901C>T
Protein change:
R301C
Links:
dbSNP: rs185492864
NCBI 1000 Genomes Browser:
rs185492864
Molecular consequence:
  • NM_001918.4:c.901C>T - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Name:
Maple syrup urine disease (MSUD)
Synonyms:
Branched chain ketoaciduria; Branched-chain alpha-keto acid dehydrogenase deficiency; Keto acid decarboxylase deficiency
Identifiers:
MONDO: MONDO:0009563; MeSH: D008375; MedGen: C0024776; Orphanet: 511; OMIM: 248600; OMIM: PS248600

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000712806Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicinecriteria provided, single submitter
Pathogenic
(Mar 28, 2017)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV000835510Invitaecriteria provided, single submitter
Pathogenic
(Oct 20, 2020)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV000893166Fulgent Genetics,Fulgent Geneticscriteria provided, single submitter
Likely pathogenic
(Oct 31, 2018)
unknownclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001194107Myriad Women's Health, Inc.criteria provided, single submitter
Likely pathogenic
(Dec 20, 2019)
unknownclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenot provided11not providednot providednot providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]
PMID:
24033266
PMCID:
PMC3995020

SSIEM 2016 Annual Symposium - Abstracts : Rome, Italy, September 2016.

[No authors listed]

J Inherit Metab Dis. 2016 Sep;39 Suppl 1:35-284. doi: 10.1007/s10545-016-9969-2. No abstract available.

PubMed [citation]
PMID:
27518768
See all PubMed Citations (7)

Details of each submission

From Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, SCV000712806.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (3)

Description

The p.Arg301Cys (NM001918.3 c.901C>T) variant in DBT has been reported in 7 comp ound heterozygous individuals with intermittent maple syrup urine disease (Brodt korb 2010, Axler 2014). This variant has been identified in 0.144% (96/66,682) o f European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.br oadinstitute.org; dbSNP rs185492864). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessi ve carrier frequency. In vitro functional studies provide some evidence that th e p.Arg301Cys variant may impact protein function (Brodtkorb 2010). In summary, this variant meets criteria to be classified as pathogenic for maple syrup urine disease in an autosomal recessive manner based upon its biallelic occurrence in affected individuals and supported by functional studies.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided1not provided1not provided

From Invitae, SCV000835510.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change replaces arginine with cysteine at codon 301 of the DBT protein (p.Arg301Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs185492864, ExAC 0.1%). This variant has been reported in combination with another DBT variant in several individuals with intermittent maple syrup urine disease (PMID: 20570198, 21098507,27518768). ClinVar contains an entry for this variant (Variation ID: 94016). Experimental studies have shown that fibroblasts derived from individuals carrying this missense change and a second rare variant in DBT have an average of 14-36% of the BCKD enzyme activity of individuals with wild-type DBT (PMID: 20570198, 21098507). This is higher than the enzyme activity observed in cells derived from individuals with classic maple syrup urine disease, which can be 1% or less (PMID: 21098507). For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Fulgent Genetics,Fulgent Genetics, SCV000893166.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Myriad Women's Health, Inc., SCV001194107.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

NM_001918.3(DBT):c.901C>T(R301C) is classified as likely pathogenic in the context of maple syrup urine disease type II. Sources cited for classification include the following: PMID 20570198, 21098507 and 24394677. Classification of NM_001918.3(DBT):c.901C>T(R301C) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 18, 2021

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