Submissions for variant NM_000709.4(BCKDHA):c.1312T>A (p.Tyr438Asn)

gnomAD frequency: 0.00013  dbSNP: rs137852870

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000079229	SCV000232982	pathogenic	not provided	2012-08-13	criteria provided, single submitter	clinical testing
GeneDx	RCV000079229	SCV000238735	pathogenic	not provided	2023-03-31	criteria provided, single submitter	clinical testing	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)
Genetic Services Laboratory, University of Chicago	RCV000002473	SCV000593618	pathogenic	Maple syrup urine disease type 1A	2015-10-05	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000079229	SCV000609670	pathogenic	not provided	2017-07-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000002473	SCV000697539	pathogenic	Maple syrup urine disease type 1A	2017-01-06	criteria provided, single submitter	clinical testing	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.
SIB Swiss Institute of Bioinformatics	RCV000055825	SCV000803565	likely pathogenic	Maple syrup urine disease	2018-05-31	criteria provided, single submitter	curation	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).
Fulgent Genetics, Fulgent Genetics	RCV000055825	SCV000894196	pathogenic	Maple syrup urine disease	2018-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV000055825	SCV000942885	pathogenic	Maple syrup urine disease	2023-12-23	criteria provided, single submitter	clinical testing	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.
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	RCV000055825	SCV001251479	pathogenic	Maple syrup urine disease		criteria provided, single submitter	research	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).
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000055825	SCV001368392	likely pathogenic	Maple syrup urine disease	2020-01-16	criteria provided, single submitter	clinical testing	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP3.
Revvity Omics, Revvity	RCV000055825	SCV002017730	pathogenic	Maple syrup urine disease	2021-09-22	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000055825	SCV002033584	pathogenic	Maple syrup urine disease	2021-11-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002514533	SCV003545434	pathogenic	Inborn genetic diseases	2021-08-25	criteria provided, single submitter	clinical testing	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.
Neuberg Centre For Genomic Medicine, NCGM	RCV000055825	SCV004101464	pathogenic	Maple syrup urine disease		criteria provided, single submitter	clinical testing	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 .
Baylor Genetics	RCV000055825	SCV004215880	pathogenic	Maple syrup urine disease	2023-09-05	criteria provided, single submitter	clinical testing
OMIM	RCV000055825	SCV000022631	pathogenic	Maple syrup urine disease	2003-08-15	no assertion criteria provided	literature only
GeneReviews	RCV000055825	SCV000086811	not provided	Maple syrup urine disease		no assertion provided	literature only
Counsyl	RCV000055825	SCV000788600	likely pathogenic	Maple syrup urine disease	2017-01-24	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000002473	SCV001461601	pathogenic	Maple syrup urine disease type 1A	2020-09-16	no assertion criteria provided	clinical testing