NM_001918.4(DBT):c.1202T>C (p.Ile401Thr) AND Maple syrup urine disease

Clinical significance:Conflicting interpretations of pathogenicity, Likely pathogenic(1);Uncertain significance(1) (Last evaluated: Sep 9, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:

Allele description [Variation Report for NM_001918.4(DBT):c.1202T>C (p.Ile401Thr)]

NM_001918.4(DBT):c.1202T>C (p.Ile401Thr)

DBT:dihydrolipoamide branched chain transacylase E2 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_001918.4(DBT):c.1202T>C (p.Ile401Thr)
  • NC_000001.11:g.100206452A>G
  • NG_011852.2:g.48402T>C
  • NM_001918.4:c.1202T>C
  • NP_001909.3:p.Ile401Thr
  • NC_000001.10:g.100672008A>G
  • NM_001918.3:c.1202T>C
Protein change:
dbSNP: rs1449113689
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_001918.4:c.1202T>C - missense variant - [Sequence Ontology: SO:0001583]


Maple syrup urine disease (MSUD)
Branched chain ketoaciduria; Branched-chain alpha-keto acid dehydrogenase deficiency; Keto acid decarboxylase deficiency
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)
SCV000792833Counsylcriteria provided, single submitter
Uncertain significance
(Jul 18, 2017)
unknownclinical testing

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

Citation Link,

SCV001575139Invitaecriteria provided, single submitter
Likely pathogenic
(Sep 9, 2020)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Summary from all submissions

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



Molecular genetics of maple syrup urine disease in the Turkish population.

Gorzelany K, Dursun A, Coşkun T, Kalkanoğlu-Sivri SH, Gökçay GF, Demirkol M, Feyen O, Wendel U.

Turk J Pediatr. 2009 Mar-Apr;51(2):97-102. Erratum in: Turk J Pediatr. 2009 Sep-Oct;51(5):525.

PubMed [citation]

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

Details of each submission

From Counsyl, SCV000792833.1

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

From Invitae, SCV001575139.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)


This sequence change replaces isoleucine with threonine at codon 401 of the DBT protein (p.Ile401Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with maple syrup urine disease (PMID: 19480318). ClinVar contains an entry for this variant (Variation ID: 552910). 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 DBT protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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

Last Updated: May 14, 2021

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