6-80171356-AT-ATT

Variant names:

• chr6-80171356-A-AT
• rs1167005638
• NM_183050.4:c.714dupT

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_183050.4(BCKDHB):​c.714dupT​(p.Glu239fs) variant causes a frameshift, stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BCKDHB NM_183050.4 frameshift, stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.25
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• maple syrup urine disease type 1B

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, G2P, Myriad Women’s Health
• maple syrup urine disease

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• classic maple syrup urine disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• intermediate maple syrup urine disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• intermittent maple syrup urine disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• thiamine-responsive maple syrup urine disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 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 6-80171356-A-AT is Pathogenic according to our data. Variant chr6-80171356-A-AT is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 527130.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	c.714dupT	p.Glu239fs	frameshift_variant, stop_gained	Exon 6 of 10	ENST00000320393.9	NP_898871.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BCKDHB	ENST00000320393.9	c.714dupT	p.Glu239fs	frameshift_variant, stop_gained	Exon 6 of 10	1	NM_183050.4	ENSP00000318351.5
BCKDHB	ENST00000356489.9	c.714dupT	p.Glu239fs	frameshift_variant, stop_gained	Exon 6 of 11	1		ENSP00000348880.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 247856 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Maple syrup urine disease Pathogenic:1

Sep 17, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Glu239*) in the BCKDHB gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BCKDHB-related disease. Loss-of-function variants in BCKDHB are known to be pathogenic (PMID: 16786533, 22593002). For these reasons, this variant has been classified as Pathogenic.

Maple syrup urine disease type 1B Pathogenic:1

Dec 22, 2023

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.2
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1167005638; hg19: chr6-80881073; COSMIC: COSV57519842; COSMIC: COSV57519842;