NM_000709.4:c.1234G>A

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_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

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 7.31

Variant links:

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]

BCKDHA links:

ENSG00000255730 (HGNC:):

ENSG00000255730 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
BCKDHA	NM_000709.4 link	c.1234G>A	p.Val412Met	missense_variant	Exon 9 of 9	ENST00000269980.7	NP_000700.1	P12694-1A0A024R0K3
BCKDHA	NM_001164783.2 link	c.1231G>A	p.Val411Met	missense_variant	Exon 9 of 9		NP_001158255.1	P12694Q59EI3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
BCKDHA	ENST00000269980.7 link	c.1234G>A	p.Val412Met	missense_variant	Exon 9 of 9	1	NM_000709.4	ENSP00000269980.2	P12694-1
ENSG00000255730	ENST00000540732.3 link	c.1336G>A	p.Val446Met	missense_variant	Exon 10 of 10	2		ENSP00000443246.1	F5H5P2
BCKDHA	ENST00000457836.6 link	c.1243G>A	p.Val415Met	missense_variant	Exon 9 of 9	2		ENSP00000416000.2	P12694-2
BCKDHA	ENST00000544905.1 link	c.63G>A	p.Thr21Thr	splice_region_variant, synonymous_variant	Exon 2 of 2	2		ENSP00000445727.1	H0YH20

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

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:

AN:

1461864

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727234

show subpopulations

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:

AN:

152144

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74318

show subpopulations

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.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Maple syrup urine disease

Pathogenic:8

Jan 01, 2011

Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

May 07, 2020

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

National Newborn Screening Laboratory, Hospital Nacional de Niños

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

Oct 13, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 27, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 15, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 21, 2017

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 07, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Maple syrup urine disease type 1A

Pathogenic:2

Sep 08, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 05, 2019

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jul 18, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Aug 25, 2013

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

.;T;.

Eigen

Pathogenic

0.74

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.95

D;D;D

M_CAP

Pathogenic

0.72

MetaRNN

Pathogenic

0.95

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.8

.;H;.

PrimateAI

Uncertain

0.77

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over