NM_183050.4(BCKDHB):c.506A>G (p.Tyr169Cys) AND Maple syrup urine disease

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Sep 21, 2023
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:: RCV001040696.24

Allele description [Variation Report for NM_183050.4(BCKDHB):c.506A>G (p.Tyr169Cys)]

NM_183050.4(BCKDHB):c.506A>G (p.Tyr169Cys)

Gene:

BCKDHB:branched chain keto acid dehydrogenase E1 subunit beta [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

6q14.1

Genomic location:

Preferred name:

NM_183050.4(BCKDHB):c.506A>G (p.Tyr169Cys)

HGVS:

NC_000006.12:g.80168903A>G
NG_009775.2:g.67277A>G
NM_000056.5:c.506A>G
NM_001318975.1:c.296A>G
NM_183050.4:c.506A>GMANE SELECT
NP_000047.1:p.Tyr169Cys
NP_001305904.1:p.Tyr99Cys
NP_898871.1:p.Tyr169Cys
NP_898871.1:p.Tyr169Cys
NC_000006.11:g.80878620A>G
NM_183050.2:c.506A>G
NM_183050.3:c.506A>G
NR_134945.2:n.529A>G

Protein change:

Y169C

Links:

dbSNP: rs398124580

NCBI 1000 Genomes Browser:

rs398124580

Molecular consequence:

NM_000056.5:c.506A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001318975.1:c.296A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_183050.4:c.506A>G - missense variant - [Sequence Ontology: SO:0001583]
NR_134945.2:n.529A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

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
SCV001204285	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Sep 8, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 31112740, 33131499, 28492532
SCV002033096	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Nov 7, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002060138	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2021))	Uncertain significance (Nov 10, 2021)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 33131499, 31112740 Citation Link,
SCV004215953	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Sep 21, 2023)	unknown	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	no	not provided	not provided	not provided	not provided	not provided	clinical testing
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

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. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Maple syrup urine disease in Brazilian patients: variants and clinical phenotype heterogeneity.

Margutti AVB, Silva WA Jr, Garcia DF, de Molfetta GA, Marques AA, Amorim T, Prazeres VMG, Boy da Silva RT, Miura IK, Seda Neto J, Santos ES, Santos MLSF, Lourenço CM, Tonon T, Sperb-Ludwig F, de Souza CFM, Schwartz IVD, Camelo JS Jr.

Orphanet J Rare Dis. 2020 Nov 1;15(1):309. doi: 10.1186/s13023-020-01590-7.

PubMed [citation]

PMID:: 33131499
PMCID:: PMC7603684

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001204285.5

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

Description

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 169 of the BCKDHB protein (p.Tyr169Cys). This variant is present in population databases (rs398124580, gnomAD 0.005%). 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 96587). This missense change has been observed in individual(s) with maple syrup urine disease (PMID: 31112740, 33131499). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant.

#	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 Genome-Nilou Lab, SCV002033096.1

#	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	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Myriad Genetics, Inc., SCV002060138.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

NM_183050.2(BCKDHB):c.506A>G(Y169C) is a missense variant classified as a variant of uncertain significance in the context of maple syrup urine disease type Ib. Y169C has been observed in cases with relevant disease (PMID: 31112740, 33131499, Park_2015_(no PMID; abstract)). Functional assessments of this variant are not available in the literature. Y169C has been observed in population frequency databases (gnomAD: EAS 0.01%). In summary, there is insufficient evidence to classify NM_183050.2(BCKDHB):c.506A>G(Y169C) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.

#	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 Baylor Genetics, SCV004215953.1

#	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

Last Updated: Nov 3, 2024

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