rs185492864

chr1-100214855-G-Achr1-100214855-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 10P and 4B. PM5 PP5_Very_Strong BS2

The NM_001918.5(DBT):c.901C>T(p.Arg301Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000279 in 1,613,930 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R301H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00028 (2 hom.)
• Consequence: DBT NM_001918.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 9.60

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-100214854-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 437447.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1}.
• PP5: Variant 1-100214855-G-A is Pathogenic according to our data. Variant chr1-100214855-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 94016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DBT	NM_001918.5	c.901C>T	p.Arg301Cys	missense_variant	7/11	ENST00000370132.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DBT	ENST00000370132.8	c.901C>T	p.Arg301Cys	missense_variant	7/11	1	NM_001918.5	P1
DBT	ENST00000370131.3	c.901C>T	p.Arg301Cys	missense_variant	7/8	1
DBT	ENST00000681617.1	c.901C>T	p.Arg301Cys	missense_variant	7/12
DBT	ENST00000681780.1	c.358C>T	p.Arg120Cys	missense_variant	8/12

Frequencies

GnomAD3 genomes AF: 0.000243 AC: 37 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.000426

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000513 AC: 129 AN: 251458 Hom.: 2 AF XY: 0.000545 AC XY: 74 AN XY: 135900

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.00104

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000283 AC: 414 AN: 1461804 Hom.: 2 Cov.: 32 AF XY: 0.000271 AC XY: 197 AN XY: 727200

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000468

Gnomad4 NFE exome AF: 0.000323

Gnomad4 OTH exome AF: 0.000430

GnomAD4 genome AF: 0.000243 AC: 37 AN: 152126 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74302

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000426

Gnomad4 OTH AF: 0.000958

Alfa AF: 0.000323 Hom.: 0

Bravo AF: 0.000230

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000799 AC: 97

EpiCase AF: 0.000273

EpiControl AF: 0.000533

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Maple syrup urine disease Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 20, 2019	NM_001918.3(DBT):c.901C>T(R301C) is classified as likely pathogenic in the context of maple syrup urine disease type II. Sources cited for classification include the following: PMID 20570198, 21098507 and 24394677. Classification of NM_001918.3(DBT):c.901C>T(R301C) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 16, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 13, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 24, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 301 of the DBT protein (p.Arg301Cys). This variant is present in population databases (rs185492864, gnomAD 0.1%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with intermittent maple syrup urine disease (PMID: 20570198, 21098507, 27518768). ClinVar contains an entry for this variant (Variation ID: 94016). 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 DBT protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects DBT function (PMID: 20570198, 21098507). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 17, 2021	Variant summary: DBT c.901C>T (p.Arg301Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00051 in 251458 control chromosomes in the gnomAD database, including 2 homozygotes. c.901C>T has been reported in the literature in multiple individuals affected with Maple Syrup Urine Disease (e.g. Brodtkorb_2010, Tangeraas_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. 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2017	The p.Arg301Cys (NM001918.3 c.901C>T) variant in DBT has been reported in 7 comp ound heterozygous individuals with intermittent maple syrup urine disease (Brodt korb 2010, Axler 2014). This variant has been identified in 0.144% (96/66,682) o f European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.br oadinstitute.org; dbSNP rs185492864). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessi ve carrier frequency. In vitro functional studies provide some evidence that th e p.Arg301Cys variant may impact protein function (Brodtkorb 2010). In summary, this variant meets criteria to be classified as pathogenic for maple syrup urine disease in an autosomal recessive manner based upon its biallelic occurrence in affected individuals and supported by functional studies. -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Dec 20, 2021	PS3, PM3_Strong, PM1 -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 26, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 20, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25087612, 20570198, 21098507, 24928662, 24394677, 34426522, 31589614, 30609409, 31980395, 33726816, 33123633, 27518768) -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 09, 2021	DNA sequence analysis of the DBT gene demonstrated a sequence change, c.901C>T, in exon 7 that results in an amino acid change, p.Arg301Cys. The p.Arg301Cys change affects a highly conserved amino acid residue located in a domain of the DBT protein that is known to be functional. The p.Arg301Cys substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This pathogenic sequence change has previously been described in multiple individuals with maple syrup urine disease in the biallelic state (PMID: 20570198). This sequence change has been described in the gnomAD database with a frequency of 0.100% in the non-Finnish European subpopulation (dbSNP rs185492864). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.0040	T
BayesDel_noAF	Pathogenic	0.17
Cadd	Pathogenic	33
Dann	Uncertain	1.0
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.074	D
MetaRNN	Uncertain	0.44	T;T
MetaSVM	Benign	-0.59	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-5.4	D;D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.045	D;D
Vest4		0.71
MVP		0.64
MPC		0.49
ClinPred		0.71	D
GERP RS		5.4
gMVP		0.70

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

Other links and lift over

dbSNP: rs185492864; hg19: chr1-100680411;