rs794727847

Positions:

• chr19-41422633-ACGAGGCCC-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000709.4(BCKDHA):​c.861_868delAGGCCCCG​(p.Gly288fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,800 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BCKDHA NM_000709.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 9.23

Genes affected

BCKDHA (HGNC:986): (branched chain keto acid dehydrogenase E1 subunit alpha) The branched-chain alpha-keto acid (BCAA) dehydrogenase (BCKD) complex is an innter mitochondrial enzyme complex that catalyzes the second major step in the catabolism of the branched-chain amino acids leucine, isoleucine, and valine. The BCKD complex consists of three catalytic components: a heterotetrameric (alpha2-beta2) branched-chain alpha-keto acid decarboxylase (E1), a dihydrolipoyl transacylase (E2), and a dihydrolipoamide dehydrogenase (E3). This gene encodes the alpha subunit of the decarboxylase (E1) component. Mutations in this gene result in maple syrup urine disease, type IA. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Sep 2009]

ENSG00000255730 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 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 19-41422633-ACGAGGCCC-A is Pathogenic according to our data. Variant chr19-41422633-ACGAGGCCC-A is described in ClinVar as [Pathogenic]. Clinvar id is 198433.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
BCKDHA	NM_000709.4	c.861_868delAGGCCCCG	p.Gly288fs	frameshift_variant	7/9	ENST00000269980.7	NP_000700.1
BCKDHA	NM_001164783.2	c.858_865delAGGCCCCG	p.Gly287fs	frameshift_variant	7/9		NP_001158255.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BCKDHA	ENST00000269980.7	c.861_868delAGGCCCCG	p.Gly288fs	frameshift_variant	7/9	1	NM_000709.4	ENSP00000269980.2
ENSG00000255730	ENST00000540732.3	c.963_970delAGGCCCCG	p.Gly322fs	frameshift_variant	8/10	2		ENSP00000443246.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461800 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 727214

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Maple syrup urine disease Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Feb 07, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 13, 2023	This sequence change creates a premature translational stop signal (p.Gly288Valfs*11) in the BCKDHA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BCKDHA are known to be pathogenic (PMID: 16786533, 22593002). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with maple syrup urine disease (PMID: 8037208, 26830710). This variant is also known as 8-bp deletion in exon 7. ClinVar contains an entry for this variant (Variation ID: 198433). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 19, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 1994	- -

Maple syrup urine disease type 1A Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 12, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Feb 09, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 28, 2020	Variant summary: BCKDHA c.861_868delAGGCCCCG (p.Gly288ValfsX11) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251376 control chromosomes. c.861_868delAGGCCCCG has been reported in the literature in individuals affected with Maple Syrup Urine Disease Type 1A and has been subsequently cited by others (example, Stojiljkovic_2016, Chuang_1994, Bell_2011, Brunetti-Pierri_2011, Hallam_2014, Umbarger_2012, Chinsky_1998, Imperlini_2016). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two 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 citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jan 28, 2015

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs794727847; hg19: chr19-41928538;