NM_000709.4(BCKDHA):c.743C>T (p.Ala248Val) AND Maple syrup urine disease

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Jun 24, 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:: RCV002248980.4

Allele description [Variation Report for NM_000709.4(BCKDHA):c.743C>T (p.Ala248Val)]

NM_000709.4(BCKDHA):c.743C>T (p.Ala248Val)

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.743C>T (p.Ala248Val)

HGVS:

NC_000019.10:g.41422260C>T
NG_013004.1:g.29472C>T
NM_000709.4:c.743C>TMANE SELECT
NM_001164783.2:c.743C>T
NP_000700.1:p.Ala248Val
NP_001158255.1:p.Ala248Val
NC_000019.9:g.41928165C>T
NC_000019.9:g.41928165C>T

Protein change:

A248V

Links:

dbSNP: rs887411374

NCBI 1000 Genomes Browser:

rs887411374

Molecular consequence:

NM_000709.4:c.743C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001164783.2:c.743C>T - 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
SCV002516242	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2019)	Likely pathogenic (May 4, 2022)	germline	clinical testing	Citation Link,
SCV003010744	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jun 24, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002516242

Mendelics

criteria provided, single submitter

(Mendelics Assertion Criteria 2019)

Likely pathogenic
(May 4, 2022)

germline

clinical testing

Citation Link,

SCV003010744

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jun 24, 2022)

germline

clinical testing

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

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

Citations

PubMed

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]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Mendelics, SCV002516242.1

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

#	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

From Invitae, SCV003010744.2

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

Description

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 248 of the BCKDHA protein (p.Ala248Val). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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 BCKDHA protein function. This variant has not been reported in the literature in individuals affected with BCKDHA-related conditions. This variant is not present in population databases (gnomAD no frequency).

#	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: Apr 6, 2024

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