rs398123490

Positions:

• chr19-41424504-G-A

Variant summary

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

The NM_000709.4(BCKDHA):​c.1234G>A​(p.Val412Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,614,008 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: BCKDHA NM_000709.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 7.31

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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.948
• PP5: Variant 19-41424504-G-A is Pathogenic according to our data. Variant chr19-41424504-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 93344.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.1234G>A	p.Val412Met	missense_variant	9/9	ENST00000269980.7	NP_000700.1
BCKDHA	NM_001164783.2	c.1231G>A	p.Val411Met	missense_variant	9/9		NP_001158255.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BCKDHA	ENST00000269980.7	c.1234G>A	p.Val412Met	missense_variant	9/9	1	NM_000709.4	ENSP00000269980.2
ENSG00000255730	ENST00000540732.3	c.1336G>A	p.Val446Met	missense_variant	10/10	2		ENSP00000443246.1
BCKDHA	ENST00000457836.6	c.1243G>A	p.Val415Met	missense_variant	9/9	2		ENSP00000416000.2
BCKDHA	ENST00000544905.1	c.63G>A	p.Thr21Thr	splice_region_variant, synonymous_variant	2/2	2		ENSP00000445727.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461864 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 727234

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152144 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74318

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000565 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Maple syrup urine disease Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 13, 2023	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 412 of the BCKDHA protein (p.Val412Met). This variant is present in population databases (rs398123490, gnomAD 0.007%). This missense change has been observed in individual(s) with maple syrup urine disease (PMID: 17922217, 21098507, 26257134). ClinVar contains an entry for this variant (Variation ID: 93344). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BCKDHA protein function. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 07, 2020	Variant summary: BCKDHA c.1234G>A (p.Val412Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249364 control chromosomes. c.1234G>A has been reported in the literature in individuals affected with Maple Syrup Urine Disease (example, Henneke_2003, Flaschker_2007, Brunetti-Pierri_2011, Gupta_2015). These data indicate that the variant is very likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (example, Flaschker_2007, Brunetti-Pierri_2011). 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/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 15, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	National Newborn Screening Laboratory, Hospital Nacional de Niños	-	This is a missense variant located within exon 9 and generates a change from the amino acid Valine to a Methionine in position 412. It is not present in population databases (GnomAD exomes; GnomAD genomes). This variant is associated in one publication with an individual with MSUD phenotype (PMID: 14517957). It was found in a compound heterozygous state in a patient with biochemical analysis supporting the diagnosis of MSUD (NBS dried blood sample: Xle: 2045umol/L, Val: 554umol/L. Pre-treatment plasma aminogram: Leu: 2747umol/L, Val: 788umol/L, Ile: 491umol/L). -
Pathogenic, criteria provided, single submitter	research	Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	Jan 01, 2011	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 27, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Aug 21, 2017	- -

Maple syrup urine disease type 1A Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 08, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	Feb 05, 2019	This variant has been previously reported in patients with Maple Syrup Urine Disease (PMID: 14517957, 17922217, 26257134, 21098507). Functional studies showed that BCKDC enzyme activity measured on skin fibroblasts from patients that were homozygous for this variant was significantly reduced (0.26% of normal control) (PMID: 21098507). The c.1234G>A (p.Val412Met) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.003% (1/30938) and thus is presumed to be rare. This variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.1234G>A (p.Val412Met) variant is classified as pathogenic. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 18, 2022

The c.1234G>A (p.V412M) alteration is located in exon 9 (coding exon 9) of the BCKDHA gene. This alteration results from a G to A substitution at nucleotide position 1234, causing the valine (V) at amino acid position 412 to be replaced by a methionine (M). Based on data from gnomAD, the A allele has an overall frequency of <0.01% (1/31384) total alleles studied. The highest observed frequency was 0.01% (1/15416) of European (non-Finnish) alleles. This alteration has been detected in the homozygous state and as compound heterozygous in trans with other pathogenic BCKDHA alterations in multiple unrelated individuals with BCKDHA-related maple syrup urine disease (Henneke, 2003; Flaschker, 2007; Brunett-Pierri, 2011; Gupta, 2015; Strauss, 2020). This amino acid position is well conserved in available vertebrate species. Based on internal structural analysis, V412M is moderately destabilizing (Li, 2007; Machius, 2006). 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

Pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 25, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	.;T;.
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	.;H;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.7	D;D;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0070	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.87
MutPred		0.79		Loss of helix (P = 0.079);.;.;
MVP		0.98
MPC		0.39
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.69
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs398123490; hg19: chr19-41930409;