chr6-80167744-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_183050.4(BCKDHB):c.410C>T(p.Ala137Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,612,746 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: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

BCKDHB
NM_183050.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 7.55

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.993

PP5

Variant 6-80167744-C-T is Pathogenic according to our data. Variant chr6-80167744-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 370949.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.410C>T	p.Ala137Val	missense_variant	Exon 4 of 10	ENST00000320393.9	NP_898871.1	P21953-1A0A140VKB3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
BCKDHB	ENST00000320393.9 link	c.410C>T	p.Ala137Val	missense_variant	Exon 4 of 10	1	NM_183050.4	ENSP00000318351.5	P21953-1
BCKDHB	ENST00000356489.9 link	c.410C>T	p.Ala137Val	missense_variant	Exon 4 of 11	1		ENSP00000348880.5	P21953-1
BCKDHB	ENST00000369760.8 link	c.410C>T	p.Ala137Val	missense_variant	Exon 4 of 6	3		ENSP00000358775.4	P21953-2

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152062

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251162

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135756

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1460684

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

726722

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000153

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152062

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74274

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000688

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Maple syrup urine disease

Pathogenic:5

Dec 05, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 137 of the BCKDHB protein (p.Ala137Val). This variant is present in population databases (rs776631396, gnomAD 0.003%). This missense change has been observed in individual(s) with maple syrup urine disease (PMID: 14567968, 16468966, 26830710, 29306928). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 370949). 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 BCKDHB protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects BCKDHB function (PMID: 14567968). For these reasons, this variant has been classified as Pathogenic. -

Nov 07, 2021

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 26, 2016

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 18, 2018

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been previously reported as disease causing in the Human Gene Mutation Database (HGMD) and is present in ClinVar database as likely pathogenic. Nellis M., et al (PMID: 14567968) showed that it was present as a compound heterozygous change in a patient with maple syrup urine disease (MSUD; OMIM#248600), type 1B. In this report it was shown that the patient had deficient activity of the branched chain a-ketoacid dehydrogenase (BCKD) complex (PMID: 14567968). The c.410C>T (p.Ala137Val) variant is present in the heterozygous state in the gnomAD population database at a very low frequency and thus is presumed to be rare. The c.410C>T (p.Ala137Val) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Analysis of the parental samples showed the mother is heterozygous and the father is negative for this variant. Based on the available evidence, the c.410C>T (p.Ala137Val) variant is classified as likely pathogenic. -

Feb 16, 2022

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.410C>T (p.Ala137Val) 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 1.2e-05 in 251162 control chromosomes. c.410C>T has been reported in the literature as homozygous and compound heterozygous genotypes in multiple individuals affected with classic features of Maple Syrup Urine Disease (example, Nellis_2003, Strauss_2006, Stojiljkovic_2016, Zeynalzadeh_2018, Khalifa_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported although individuals homozygous for this variant displayed all the classic biochemical profiles characteristic of Maple Syrup Urine Disease (example, Zeynalzadeh_2018, Khalifa_2020). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Maple syrup urine disease type 1B

Pathogenic:1

Feb 17, 2021

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Maple syrup urine disease type 1A

Pathogenic:1

Mar 26, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.89

.;D;D

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.99

D;.;D

M_CAP

Pathogenic

0.65

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.4

H;H;H

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-3.8

D;D;D

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

.;D;D

Vest4

0.98

MutPred

0.95

Loss of helix (P = 0.2271);Loss of helix (P = 0.2271);Loss of helix (P = 0.2271);

MVP

0.99

MPC

0.76

ClinPred

1.0

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.97

gMVP

0.99

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over