NM_183050.4(BCKDHB):c.509G>A (p.Arg170His) AND Maple syrup urine disease

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Jan 25, 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:: RCV000179047.27

Allele description [Variation Report for NM_183050.4(BCKDHB):c.509G>A (p.Arg170His)]

NM_183050.4(BCKDHB):c.509G>A (p.Arg170His)

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.509G>A (p.Arg170His)

HGVS:

NC_000006.12:g.80168906G>A
NG_009775.2:g.67280G>A
NM_000056.5:c.509G>A
NM_001318975.1:c.299G>A
NM_183050.4:c.509G>AMANE SELECT
NP_000047.1:p.Arg170His
NP_001305904.1:p.Arg100His
NP_898871.1:p.Arg170His
NP_898871.1:p.Arg170His
NC_000006.11:g.80878623G>A
NM_183050.2:c.509G>A
NM_183050.3:c.509G>A
NR_134945.2:n.532G>A
P21953:p.Arg170His

Protein change:

R100H

Links:

UniProtKB: P21953#VAR_068348; dbSNP: rs371518124

NCBI 1000 Genomes Browser:

rs371518124

Molecular consequence:

NM_000056.5:c.509G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001318975.1:c.299G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_183050.4:c.509G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_134945.2:n.532G>A - 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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000955135	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 25, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 22326532, 25381949, 26453840, 27682710, 28492532
SCV002014912	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Oct 14, 2021)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 31980395, 25381949, 33300147, 28197878, 22326532 Citation Link,
SCV002033107	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 7, 2021)	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

SCV000955135

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 25, 2024)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV002014912

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Oct 14, 2021)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link,

SCV002033107

Genome-Nilou Lab

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Nov 7, 2021)

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	no	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
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Eleven novel mutations of the BCKDHA, BCKDHB and DBT genes associated with maple syrup urine disease in the Chinese population: Report on eight cases.

Li X, Ding Y, Liu Y, Ma Y, Song J, Wang Q, Li M, Qin Y, Yang Y.

Eur J Med Genet. 2015 Nov;58(11):617-23. doi: 10.1016/j.ejmg.2015.10.002. Epub 2015 Oct 8.

PubMed [citation]

PMID:: 26453840

Co-existence of phenylketonuria either with maple syrup urine disease or Sandhoff disease in two patients from Iran: emphasizing the role of consanguinity.

Abiri M, Talebi S, Uitto J, Youssefian L, Vahidnezhad H, Shirzad T, Salehpour S, Zeinali S.

J Pediatr Endocrinol Metab. 2016 Oct 1;29(10):1215-1219. doi: 10.1515/jpem-2016-0096.

PubMed [citation]

PMID:: 27682710

See all PubMed Citations (9)

Details of each submission

From Counsyl, SCV000800532.1

#	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, SCV000955135.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 170 of the BCKDHB protein (p.Arg170His). This variant is present in population databases (rs371518124, gnomAD 0.01%). This missense change has been observed in individual(s) with BCKDHB-related conditions (PMID: 22326532; Invitae). ClinVar contains an entry for this variant (Variation ID: 96591). 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. This variant disrupts the p.Arg170 amino acid residue in BCKDHB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25381949, 26453840, 27682710). 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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002014912.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

Variant summary: BCKDHB c.509G>A (p.Arg170His) results in a non-conservative amino acid change located in the Transketolase-like, pyrimidine-binding domain (IPR005475) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251526 control chromosomes (gnomAD and publication data). c.509G>A has been reported in the literature in multiple individuals affected with Maple Syrup Urine Disease, including two homozygotes (Wang_2012, Miryounesi_2015, Strauss_2020, OReilly_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=1) and pathogenic (n=3). Based on the evidence outlined above, the variant was 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

From Genome-Nilou Lab, SCV002033107.1

#	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

Flagged submissions

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000800532	Counsyl	flagged submission Reason: Outlier claim with insufficient supporting evidence Notes: None (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Uncertain significance (May 16, 2017)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000800532

Counsyl

flagged submission

Reason: Outlier claim with insufficient supporting evidence

Notes: None

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

Uncertain significance
(May 16, 2017)

unknown

clinical testing

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

Citation Link

Last Updated: Oct 13, 2024

ClinVar

Relating variation to medicine