ClinVar Miner

Submissions for variant NM_000709.4(BCKDHA):c.1312T>A (p.Tyr438Asn) (rs137852870)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000079229 SCV000232982 pathogenic not provided 2012-08-13 criteria provided, single submitter clinical testing
GeneDx RCV000079229 SCV000238735 pathogenic not provided 2017-06-13 criteria provided, single submitter clinical testing The Y438N variant in the BCKDHA gene is a common pathogenic variant associated with maple syrup urine disease (MSUD) in the Old Order Mennonite population and is associated with a classic MSUD phenotype in homozygous individuals (Fisher et al., 1991; Puffenberger et al. 2003). Functional studies found that Y438N is associated with very low enzyme activity and no expression of the beta (E1b) subunits and very low expression of the alpha (E1a) subunits of the branched-chain alpha-ketoacid dehydrogenase complex (Matsuda et al. 1990). Therefore we interpret Y438N as a pathogenic variant.
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
Integrated Genetics/Laboratory Corporation of America 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.
Counsyl RCV000055825 SCV000788600 likely pathogenic Maple syrup urine disease 2017-01-24 criteria provided, single submitter clinical testing
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 2018-11-30 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with asparagine at codon 438 of the BCKDHA protein (p.Tyr438Asn). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and asparagine. This variant is present in population databases (rs137852870, ExAC 0.009%). This variant has been reported in several individuals affected with maple syrup urine disease (PMID: 2703538, 28170084, 11825067, 26830710) being a well known founder MSUD mutation in the Mennonites population (PMID: 11825067, 12888983, 20136525). This variant is also known as Y393N. ClinVar contains an entry for this variant (Variation ID: 100009). Experimental studies have shown that this missense change disrupts BCKDHA enzymatic function (PMID: 1885764). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000002473 SCV000022631 pathogenic Maple syrup urine disease type 1A 2003-08-15 no assertion criteria provided literature only
GeneReviews RCV000055825 SCV000086811 pathologic Maple syrup urine disease 2013-05-09 no assertion criteria provided curation Converted during submission to Pathogenic.

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