6-80106695-T-C

Variant names:

• chr6-80106695-T-C
• rs940391887
• NM_183050.4:c.2T>C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1_Supporting PM2 PP5_Very_Strong

The NM_183050.4(BCKDHB):​c.2T>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BCKDHB NM_183050.4 start_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 3.08

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 11 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 71 codons. Genomic position: 80127561. Lost 0.179 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-80106695-T-C is Pathogenic according to our data. Variant chr6-80106695-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 553562.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.2T>C	p.Met1?	start_lost	Exon 1 of 10	ENST00000320393.9	NP_898871.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BCKDHB	ENST00000320393.9	c.2T>C	p.Met1?	start_lost	Exon 1 of 10	1	NM_183050.4	ENSP00000318351.5
BCKDHB	ENST00000356489.9	c.2T>C	p.Met1?	start_lost	Exon 1 of 11	1		ENSP00000348880.5
BCKDHB	ENST00000369760.8	c.2T>C	p.Met1?	start_lost	Exon 1 of 6	3		ENSP00000358775.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Maple syrup urine disease Pathogenic:3

Jan 24, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BCKDHB c.2T>C (p.Met1Thr) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. The next downstream in-frame initiation codon is at codon 71. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 155290 control chromosomes. c.2T>C has been reported in the literature in at-least one compound heterozygous individual affected with Maple Syrup Urine Disease (example: Chen_2023). Other variants affecting the initiation codon, as well as missense variants upstream of codon 71, have been classified as pathogenic in ClinVar. 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: 37421976). ClinVar contains an entry for this variant (Variation ID: 553562). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Aug 09, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 553562). Disruption of the initiator codon has been observed in individual(s) with maple syrup urine disease (PMID: 26257134, 31980395, 32515140, 33300147; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the BCKDHB mRNA. The next in-frame methionine is located at codon 71. -

Aug 29, 2017

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.41
CADD	Benign	22
DANN	Benign	0.91
DEOGEN2	Benign	0.28	.;T;T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.098
FATHMM_MKL	Benign	0.54	D
LIST_S2	Uncertain	0.90	D;.;D
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Uncertain	0.30	D
PROVEAN	Benign	-0.67	N;N;N
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.12	.;B;B
Vest4		0.83
MutPred		0.84		Loss of stability (P = 0.0404);Loss of stability (P = 0.0404);Loss of stability (P = 0.0404);
MVP		0.98
ClinPred		1.0	D
GERP RS		4.2
Varity_R		0.92
gMVP		0.68

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: rs940391887; hg19: chr6-80816412;