6-80168905-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_183050.4(BCKDHB):c.508C>T(p.Arg170Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000015 in 1,461,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. 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. R170H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: BCKDHB NM_183050.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 5.73

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_183050.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-80168905-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 96589.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant 6-80168905-C-T is Pathogenic according to our data. Variant chr6-80168905-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 96590.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BCKDHB	NM_183050.4	c.508C>T	p.Arg170Cys	missense_variant	5/10	ENST00000320393.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCKDHB	ENST00000320393.9	c.508C>T	p.Arg170Cys	missense_variant	5/10	1	NM_183050.4	P1
BCKDHB	ENST00000356489.9	c.508C>T	p.Arg170Cys	missense_variant	5/11	1		P1
BCKDHB	ENST00000369760.8	c.508C>T	p.Arg170Cys	missense_variant	5/6	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251436 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135892

Gnomad AFR exome AF: 0.00

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000150 AC: 22 AN: 1461848 Hom.: 0 Cov.: 34 AF XY: 0.0000165 AC XY: 12 AN XY: 727230

Gnomad4 AFR exome AF: 0.00

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: 0.0000189

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Maple syrup urine disease Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 23, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 30, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 09, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 170 of the BCKDHB protein (p.Arg170Cys). This variant is present in population databases (rs398124581, gnomAD 0.002%). This missense change has been observed in individual(s) with maple syrup urine disease (PMID: 25381949, 26453840, 27682710, 29307017). 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: 96590). 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 observed in individuals with BCKDHB-related conditions (PMID: 22326532; Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 21, 2022

The c.508C>T (p.R170C) alteration is located in exon 5 (coding exon 5) of the BCKDHB gene. This alteration results from a C to T substitution at nucleotide position 508, causing the arginine (R) at amino acid position 170 to be replaced by a cysteine (C). Based on data from gnomAD, the T allele has an overall frequency of 0.001% (2/251436) total alleles studied. The highest observed frequency was 0.002% (2/113724) of European (non-Finnish) alleles. This variant has been identified in the homozygous and compound heterozygous state in several individuals with maple syrup urine disease (Li, 2015; Miryounesi, 2015; Abiri, 2017; Li, 2018; Fang, 2021; Martín-Rivada, 2022). In addition, multiple different variants at this amino acid position have been detected in patients with maple syrup urine disease including p.R170H (c.509G>A), p.R170G (c.508C>G), and p.R170P (c.509G>C)(Strauss, 2020; O'Reilly, 2021; Wang, 2012; ClinVar database). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Sep 17, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.43
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.82
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;.;D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.5	H;H;H
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-7.9	D;D;D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.98
MutPred		0.86		Loss of methylation at R170 (P = 0.0354);Loss of methylation at R170 (P = 0.0354);Loss of methylation at R170 (P = 0.0354);
MVP		0.99
MPC		0.91
ClinPred		1.0	D
GERP RS		4.2
Varity_R		0.95
gMVP		0.95

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: rs398124581; hg19: chr6-80878622; COSMIC: COSV57514512;