rs398124560

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong

The NM_183050.4(BCKDHB):c.1006G>A(p.Gly336Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,324 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

BCKDHB
NM_183050.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 6.27

Publications

6 publications found

Variant links:

Genes affected

BCKDHB (HGNC:987): (branched chain keto acid dehydrogenase E1 subunit beta) This gene encodes the E1 beta subunit of branched-chain keto acid dehydrogenase, which is a multienzyme complex associated with the inner membrane of mitochondria. This enzyme complex functions in the catabolism of branched-chain amino acids. Mutations in this gene have been associated with maple syrup urine disease (MSUD), type 1B, a disease characterized by a maple syrup odor to the urine in addition to mental and physical retardation and feeding problems. Alternative splicing at this locus results in multiple transcript variants. [provided by RefSeq, Jan 2016]

BCKDHB Gene-Disease associations (from GenCC):

maple syrup urine disease type 1B
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, G2P, Myriad Women’s Health
maple syrup urine disease
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
classic maple syrup urine disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
intermediate maple syrup urine disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
intermittent maple syrup urine disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
thiamine-responsive maple syrup urine disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

BCKDHB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 17 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_183050.4

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 51 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Gene score misZ: -0.17637 (below the threshold of 3.09). Trascript score misZ: -0.0026186 (below the threshold of 3.09). GenCC associations: The gene is linked to classic maple syrup urine disease, thiamine-responsive maple syrup urine disease, intermittent maple syrup urine disease, intermediate maple syrup urine disease, maple syrup urine disease type 1B, maple syrup urine disease.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.991

PP5

Variant 6-80273189-G-A is Pathogenic according to our data. Variant chr6-80273189-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 96562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BCKDHB	NM_183050.4 link	c.1006G>A	p.Gly336Ser	missense_variant	Exon 9 of 10	ENST00000320393.9	NP_898871.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
BCKDHB	ENST00000320393.9 link	c.1006G>A	p.Gly336Ser	missense_variant	Exon 9 of 10	1	NM_183050.4	ENSP00000318351.5
BCKDHB	ENST00000356489.9 link	c.1006G>A	p.Gly336Ser	missense_variant	Exon 9 of 11	1		ENSP00000348880.5
BCKDHB	ENST00000468520.1 link	n.236G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 3 of 3	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

250950

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461324

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726954

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33460

American (AMR)

AF:

0.00

AC:

AN:

44674

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26102

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39664

South Asian (SAS)

AF:

0.00

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111660

Other (OTH)

AF:

0.0000331

AC:

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Maple syrup urine disease

Pathogenic:3

Nov 07, 2021

Genome-Nilou Lab

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Dec 01, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 336 of the BCKDHB protein (p.Gly336Ser). This variant is present in population databases (rs398124560, gnomAD 0.006%). This missense change has been observed in individual(s) with maple syrup urine disease (PMID: 28417071, 28830848, 31112740). ClinVar contains an entry for this variant (Variation ID: 96562). 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 not expected to disrupt BCKDHB protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.

May 28, 2019

Mendelics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Maple syrup urine disease type 1B

Pathogenic:3

Mar 25, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 18, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 05, 2023

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: BCKDHB c.1006G>A (p.Gly336Ser) results in a non-conservative amino acid change located in the C-terminal domain (IPR033248) 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 4e-06 in 251350 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1006G>A has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Maple Syrup Urine Disease Type 1B (e.g., Imtiaz_2017, Cheng_2017). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 28830848, 28417071). Five submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic (n = 1) or likely pathogenic (n = 4). Based on the evidence outlined above, the variant was classified as pathogenic.

Maple syrup urine disease type 1A

Pathogenic:2

May 16, 2018

Counsyl

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Mar 10, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Pathogenic:1

Dec 07, 2017

Eurofins Ntd Llc (ga)

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.46

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.78

D;D

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.0

.;D

M_CAP

Pathogenic

0.53

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

1.7

L;L

PhyloP100

6.3

PrimateAI

Uncertain

0.66

PROVEAN

Pathogenic

-5.7

D;D

REVEL

Pathogenic

0.92

Sift

Uncertain

0.026

D;D

Sift4G

Uncertain

0.050

T;T

Vest4

0.97

ClinPred

0.99

GERP RS

5.5

Varity_R

0.88

gMVP

0.93

Mutation Taster

=7/93

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over