NM_000709.4(BCKDHA):c.745G>A (p.Gly249Ser) AND Maple syrup urine disease

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Jan 31, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001064270.11

Allele description [Variation Report for NM_000709.4(BCKDHA):c.745G>A (p.Gly249Ser)]

NM_000709.4(BCKDHA):c.745G>A (p.Gly249Ser)

Gene:

BCKDHA:branched chain keto acid dehydrogenase E1 subunit alpha [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19q13.2

Genomic location:

Preferred name:

NM_000709.4(BCKDHA):c.745G>A (p.Gly249Ser)

Other names:

G204S

HGVS:

NC_000019.10:g.41422262G>A
NG_013004.1:g.29474G>A
NM_000709.4:c.745G>AMANE SELECT
NM_001164783.2:c.745G>A
NP_000700.1:p.Gly249Ser
NP_001158255.1:p.Gly249Ser
NC_000019.9:g.41928167G>A
NM_000709.3:c.745G>A

Protein change:

G249S; GLY204SER

Links:

OMIM: 608348.0006; dbSNP: rs137852874

NCBI 1000 Genomes Browser:

rs137852874

Molecular consequence:

NM_000709.4:c.745G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001164783.2:c.745G>A - 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
SCV000022637	OMIM	no assertion criteria provided	Pathogenic (May 22, 1998)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV001229159	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jan 31, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 20431954, 31980395, 9582350, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000022637

OMIM

no assertion criteria provided

Pathogenic
(May 22, 1998)

germline

literature only

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

SCV001229159

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jan 31, 2024)

germline

clinical testing

PubMed (4)
[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	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Functional characterization of the novel intronic nucleotide change c.288+9C>T within the BCKDHA gene: understanding a variant presentation of maple syrup urine disease.

Fernández-Guerra P, Navarrete R, Weisiger K, Desviat LR, Packman S, Ugarte M, Rodríguez-Pombo P.

J Inherit Metab Dis. 2010 Dec;33 Suppl 3:S191-8. doi: 10.1007/s10545-010-9077-7. Epub 2010 Apr 30.

PubMed [citation]

PMID:: 20431954

Branched-chain α-ketoacid dehydrogenase deficiency (maple syrup urine disease): Treatment, biomarkers, and outcomes.

Strauss KA, Carson VJ, Soltys K, Young ME, Bowser LE, Puffenberger EG, Brigatti KW, Williams KB, Robinson DL, Hendrickson C, Beiler K, Taylor CM, Haas-Givler B, Chopko S, Hailey J, Muelly ER, Shellmer DA, Radcliff Z, Rodrigues A, Loeven K, Heaps AD, Mazariegos GV, et al.

Mol Genet Metab. 2020 Mar;129(3):193-206. doi: 10.1016/j.ymgme.2020.01.006. Epub 2020 Jan 16.

PubMed [citation]

PMID:: 31980395

See all PubMed Citations (4)

Details of each submission

From OMIM, SCV000022637.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In fibroblasts derived from a patient with classic maple syrup urine disease (MSUD1A; 248600), Wynn et al. (1998) identified compound heterozygosity for 2 mutations in the BCKDHA gene: a G-to-A transition resulting in a gly204-to-ser (G204S) substitution and Y393N (608348.0001). Detailed functional expression studies in E. coli found that the G204S protein showed slow assembly kinetics with the E1-beta subunit compared to wildtype (over 2 hours versus 10 to 20 minutes), although tetramers were formed. Enzyme activity was undetectable and the G204S protein showed decreased thermal stability compared to wildtype.

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

From Invitae, SCV001229159.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 249 of the BCKDHA protein (p.Gly249Ser). This variant is present in population databases (rs137852874, gnomAD 0.003%). This missense change has been observed in individual(s) with maple syrup urine disease (PMID: 9582350, 20431954, 31980395). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as Gly204Ser. ClinVar contains an entry for this variant (Variation ID: 2380). 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 BCKDHA protein function. Experimental studies have shown that this missense change affects BCKDHA function (PMID: 9582350). 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.

#	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 16, 2024

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