rs74103423

Positions:

chr1-100216085-C-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001918.5(DBT):c.670G>T(p.Glu224Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000372 in 1,613,696 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

DBT
NM_001918.5 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 6.89

Variant links:

Genes affected

DBT (HGNC:2698): (dihydrolipoamide branched chain transacylase E2) The branched-chain alpha-keto acid dehydrogenase complex (BCKD) is an inner-mitochondrial enzyme complex involved in the breakdown of the branched-chain amino acids isoleucine, leucine, and valine. The BCKD complex is thought to be composed of a core of 24 transacylase (E2) subunits, and associated decarboxylase (E1), dehydrogenase (E3), and regulatory subunits. This gene encodes the transacylase (E2) subunit. Mutations in this gene result in maple syrup urine disease, type 2. Alternatively spliced transcript variants have been described, but their biological validity has not been determined. [provided by RefSeq, Jul 2008]

DBT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-100216085-C-A is Pathogenic according to our data. Variant chr1-100216085-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 94009.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DBT	NM_001918.5 linkuse as main transcript	c.670G>T	p.Glu224Ter	stop_gained	6/11	ENST00000370132.8	NP_001909.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
DBT	ENST00000370132.8 linkuse as main transcript	c.670G>T	p.Glu224Ter	stop_gained	6/11	1	NM_001918.5	ENSP00000359151	P1
DBT	ENST00000370131.3 linkuse as main transcript	c.670G>T	p.Glu224Ter	stop_gained	6/8	1		ENSP00000359150
DBT	ENST00000681617.1 linkuse as main transcript	c.670G>T	p.Glu224Ter	stop_gained	6/12			ENSP00000505544
DBT	ENST00000681780.1 linkuse as main transcript	c.127G>T	p.Glu43Ter	stop_gained	7/12			ENSP00000505780

Frequencies

GnomAD3 genomes

AF:

0.000243

AC:

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000893

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000636

AC:

AN:

251466

Hom.:

AF XY:

0.0000662

AC XY:

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.000984

Gnomad AMR exome

AF:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000157

AC:

AN:

1461472

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

727060

show subpopulations

Gnomad4 AFR exome

AF:

0.000657

Gnomad4 AMR exome

AF:

0.00

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:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.000243

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.000891

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:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000615

Hom.:

Bravo

AF:

0.000162

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000906

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3476

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Maple syrup urine disease

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 02, 2024	This sequence change creates a premature translational stop signal (p.Glu224*) in the DBT gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DBT are known to be pathogenic (PMID: 16579849, 16786533). This variant is present in population databases (rs74103423, gnomAD 0.1%). This premature translational stop signal has been observed in individuals with maple syrup urine disease (PMID: 8430702). ClinVar contains an entry for this variant (Variation ID: 94009). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 11, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Nov 03, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 29, 2024	The p.Glu224X variant (also described as p.Glu163X as a legacy nomenclature) in DBT has been reported in at least 6 individuals in the homozygous or compound heterozygous state with maple syrup urine disease (MSUD), where BCKD enzyme activity was markedly reduced in at least 3 individuals (Fisher 1993 PMID: 8430702, Khalifa 2020 PMID: 32812330). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 94009) and has been identified in 0.09% (37/41420) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). This nonsense variant leads to a premature termination codon at position 43, which is predicted to lead to a truncated or absent protein. This is corroborated by in vitro functional studies that show a truncated protein in patients with MSUD compared with full-length wildtype (Fisher 1993 PMID: 8430702). Biallelic loss of function of the DBT gene is an established disease mechanism in autosomal recessive MSUD. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive MSUD. ACMG/AMP Criteria applied: PVS1_Moderate, PM3, PS3_Supporting, PP4. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 20, 2024	Variant summary: DBT c.670G>T (p.Glu224X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 6.4e-05 in 251466 control chromosomes. c.670G>T has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Maple Syrup Urine Disease (e.g., Fisher_1993). 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. The following publication has been ascertained in the context of this evaluation (PMID: 8430702). ClinVar contains an entry for this variant (Variation ID: 94009). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 23, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 23, 2023	Functional studies demonstrate that cell lines with the E224X variant result in a markedly truncated polypeptide compared with full-length wildtype (Fisher et al., 1993); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 8430702, 25087612, 25525159, 31980395, 32812330, 31589614, 31345219) -

Maple syrup urine disease type 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

DASA

Nov 03, 2022

The c.670G>T;p.(Glu224*) variant creates a premature translational stop signal in the DBT gene. It is expected to result in an absent or disrupted protein product - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 94009; PMID: 32812330) - PS4. The variant is present at low allele frequencies population databases (rs74103423 – gnomAD 0.0009193%; ABraOM 0.000427 frequency - https://abraom.ib.usp.br/) - PM2_supporting. In summary, the currently available evidence indicates that the variant is pathogenic. -

Maple syrup urine disease type 1A

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 27, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.65

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.98

MutationTaster

Benign

1.0

A;A

Vest4

0.94

GERP RS

4.8

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