rs137852870
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong
The NM_000709.4(BCKDHA):c.1312T>A(p.Tyr438Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000571 in 1,611,804 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y438H) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000709.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BCKDHA | NM_000709.4 | c.1312T>A | p.Tyr438Asn | missense_variant | 9/9 | ENST00000269980.7 | |
BCKDHA | NM_001164783.2 | c.1309T>A | p.Tyr437Asn | missense_variant | 9/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BCKDHA | ENST00000269980.7 | c.1312T>A | p.Tyr438Asn | missense_variant | 9/9 | 1 | NM_000709.4 | P1 | |
BCKDHA | ENST00000457836.6 | c.1321T>A | p.Tyr441Asn | missense_variant | 9/9 | 2 | |||
BCKDHA | ENST00000544905.1 | c.144T>A | p.Thr48= | synonymous_variant | 2/2 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.000118 AC: 18AN: 152154Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000643 AC: 16AN: 248834Hom.: 0 AF XY: 0.0000521 AC XY: 7AN XY: 134482
GnomAD4 exome AF: 0.0000507 AC: 74AN: 1459650Hom.: 0 Cov.: 35 AF XY: 0.0000524 AC XY: 38AN XY: 725838
GnomAD4 genome ? AF: 0.000118 AC: 18AN: 152154Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10AN XY: 74312
ClinVar
Submissions by phenotype
Maple syrup urine disease Pathogenic:10Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The missense variant c.1312T>A (p.Tyr438Asn) in BCKDHA gene has been observed in individual(s) with maple syrup urine disease (Latisha D Love-Gregory et.al.,2002). Experimental studies have shown that this missense change affects BCKDHA function (Stojiljkovic M et.al 2016). This variant has been reported to the ClinVar database as Pathogenic/Likely_pathogenic. The p.Tyr438Asn variant is reported with allele frequency 0.007% in gnomAD exomes and novel in 1000 Genomes. The amino acid Tyr at position 438 is changed to a Asn changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic . - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 16, 2020 | This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP3. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 15, 2003 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Likely pathogenic, criteria provided, single submitter | curation | SIB Swiss Institute of Bioinformatics | May 31, 2018 | This variant is interpreted as a Likely Pathogenic, for Maple syrup urine disease, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3 => Well-established functional studies show a deleterious effect (PMID:1885764). - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 22, 2021 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Jan 24, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 23, 2023 | This sequence change replaces tyrosine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 438 of the BCKDHA protein (p.Tyr438Asn). This variant is present in population databases (rs137852870, gnomAD 0.02%). This missense change has been observed in individual(s) with maple syrup urine disease (PMID: 2703538, 11825067, 12888983, 20136525, 26830710, 28170084). It has also been observed to segregate with disease in related individuals. This variant is also known as Y393N. ClinVar contains an entry for this variant (Variation ID: 100009). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BCKDHA function (PMID: 1885764). For these reasons, this variant has been classified as Pathogenic. - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | research | UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill | - | The BCKDHA c.1312T>A (p.Y438N) variant (also called Y393N) is a pathogenic founder variant associated with maple syrup urine disease (MSUD) in the Old Order Mennonite population. The p.Y438N variant has been associated with classical MSUD in a homozygous state, and in non-Mennonite individuals in a compound heterozygous state. This variant has been shown to destabilize the E1 catalytic subunit of the branched-chain alpha-keto acid dehydrogenase complex and was associated with very low enzyme activity (PMID: 1885764; 2241958; 2703538; 11825067; 26830710). - |
Maple syrup urine disease type 1A Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 30, 2024 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 06, 2017 | Variant summary: The BCKDHA c.1312T>A (p.Tyr438Asn) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this substitution. This variant was found in 6/119260 control chromosomes at a frequency of 0.0000503, which does not exceed the estimated maximal expected allele frequency of a pathogenic BCKDHA variant (0.0016771). It was reported in several MSUD patients in either homozygosity or in compound heterozygosity with other disease causing variants indicating pathogenicity. Moreover, the c.1312T>A is considered to be a founder mutation in certain Mennonite populations (GeneReviews). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Oct 05, 2015 | - - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Jul 05, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 13, 2012 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 31, 2023 | Published functional studies found this variant is associated with significantly reduced enzyme activity (Fisher CR et al., 1991); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(Y393N); This variant is associated with the following publications: (PMID: 14517957, 26830710, 11825067, 24268812, 21228398, 25087612, 19456321, 19715473, 11486905, 18378174, 21844576, 12888983, 7707687, 16468966, 2703538, 28170084, 31028937, 31589614, 32853555, 25255367, 22593002, 33996492, 32812330, 31980395, 1867199, 2241958, 1885764) - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 25, 2021 | The c.1312T>A (p.Y438N) alteration is located in exon 9 (coding exon 9) of the BCKDHA gene. This alteration results from a T to A substitution at nucleotide position 1312, causing the tyrosine (Y) at amino acid position 438 to be replaced by an asparagine (N). Based on data from gnomAD, the A allele has an overall frequency of 0.01% (21/280202) total alleles studied. The highest observed frequency was 0.02% (21/127306) of European (non-Finnish) alleles. This mutation, also referred to as Y393N in the literature, has been reported in the homozygous state in several patients with maple syrup urine disease and is a founder mutation with an estimated carrier frequency of approximately 8% in the Old Order Mennonite population (Fisher, 1991a; Puffenberger, 2003; Khalifa, 2020). In vitro functional studies demonstrated that this mutation impedes assembly of the E1α and E1β subunits (Fisher, 1991b). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at