NM_001918.5(DBT):c.788T>C (p.Met263Thr) AND Maple syrup urine disease

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Jul 25, 2022
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000667766.5

Allele description [Variation Report for NM_001918.5(DBT):c.788T>C (p.Met263Thr)]

NM_001918.5(DBT):c.788T>C (p.Met263Thr)

Gene:

DBT:dihydrolipoamide branched chain transacylase E2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p21.2

Genomic location:

Preferred name:

NM_001918.5(DBT):c.788T>C (p.Met263Thr)

HGVS:

NC_000001.11:g.100214968A>G
NG_011852.2:g.39886T>C
NM_001918.5:c.788T>CMANE SELECT
NP_001909.4:p.Met263Thr
NC_000001.10:g.100680524A>G
NM_001918.3:c.788T>C

Protein change:

M263T

Links:

dbSNP: rs1553230703

NCBI 1000 Genomes Browser:

rs1553230703

Molecular consequence:

NM_001918.5:c.788T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Maple syrup urine disease (MSUD)
Identifiers:: MONDO: MONDO:0009563; MeSH: D008375; MedGen: C0024776; Orphanet: 511; OMIM: PS248600

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000792270	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Uncertain significance (Jun 21, 2017)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV003523233	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 25, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 16786533, 19480318, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000792270

Counsyl

criteria provided, single submitter

(Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))

Uncertain significance
(Jun 21, 2017)

unknown

clinical testing

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

Citation Link,

SCV003523233

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jul 25, 2022)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutational spectrum of maple syrup urine disease in Spain.

Rodríguez-Pombo P, Navarrete R, Merinero B, Gómez-Puertas P, Ugarte M.

Hum Mutat. 2006 Jul;27(7):715.

PubMed [citation]

PMID:: 16786533

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]

PMID:: 19480318

See all PubMed Citations (3)

Details of each submission

From Counsyl, SCV000792270.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003523233.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

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. ClinVar contains an entry for this variant (Variation ID: 552494). This missense change has been observed in individual(s) with maple syrup urine disease (PMID: 16786533). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 263 of the DBT protein (p.Met263Thr). This variant disrupts the p.Met263 amino acid residue in DBT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19480318). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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