rs749033513

Positions:

• chr6-80168900-G-A
• chr6-80168900-G-C
• chr6-80168900-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_183050.4(BCKDHB):​c.503G>A​(p.Arg168His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,846 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 (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BCKDHB NM_183050.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 9.49

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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 6-80168900-G-A is Pathogenic according to our data. Variant chr6-80168900-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 457149.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
BCKDHB	NM_183050.4	c.503G>A	p.Arg168His	missense_variant	5/10	ENST00000320393.9	NP_898871.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BCKDHB	ENST00000320393.9	c.503G>A	p.Arg168His	missense_variant	5/10	1	NM_183050.4	ENSP00000318351	P1
BCKDHB	ENST00000356489.9	c.503G>A	p.Arg168His	missense_variant	5/11	1		ENSP00000348880	P1
BCKDHB	ENST00000369760.8	c.503G>A	p.Arg168His	missense_variant	5/6	3		ENSP00000358775

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461846 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727224

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Maple syrup urine disease Pathogenic:4

Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Feb 13, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 16, 2022	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 457149). This missense change has been observed in individual(s) with maple syrup urine disease (PMID: 16786533, 26232051, 28197878; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 168 of the BCKDHB protein (p.Arg168His). -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 23, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 25, 2023	Variant summary: BCKDHB c.503G>A (p.Arg168His) 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 was absent in 251412 control chromosomes (gnomAD). c.503G>A has been reported in the literature in both homozygous and compound heterozygous individuals affected with Maple Syrup Urine Disease (e.g., Rodriguez-Pombo_2006, Couce_2015, Su_2017). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in <1% BCKD activity in homozygous patient cells (e.g., Rodriguez-Pombo_2006). The following publications have been ascertained in the context of this evaluation (PMID: 26232051, 16786533, 28197878). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic (n = 2) or likely pathogenic (n = 1). Additionally, another missense variant impacting the same amino acid, c.502C>T (p.R168C), has been classified as pathogenic by our lab. Based on the evidence outlined above, the variant was classified as pathogenic. -

Maple syrup urine disease type 1B Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Dec 22, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.73	.;D;D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;.;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Uncertain	2.3	M;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-4.9	D;D;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0090	D;D;D
Sift4G	Uncertain	0.010	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.97
MutPred		0.97		Loss of phosphorylation at S171 (P = 0.1724);Loss of phosphorylation at S171 (P = 0.1724);Loss of phosphorylation at S171 (P = 0.1724);
MVP		0.99
MPC		0.72
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.90
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: rs749033513; hg19: chr6-80878617;