Submissions for variant NM_000709.4(BCKDHA):c.868G>A (p.Gly290Arg)

gnomAD frequency: 0.00001  dbSNP: rs137852871

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000790729	SCV000232081	pathogenic	not provided	2013-08-25	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	RCV000179775	SCV000240047	pathogenic	Maple syrup urine disease	2013-01-01	criteria provided, single submitter	research
Counsyl	RCV000179775	SCV000790577	likely pathogenic	Maple syrup urine disease	2017-03-29	criteria provided, single submitter	clinical testing
SIB Swiss Institute of Bioinformatics	RCV000179775	SCV000803477	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:7883996,9582350).
Invitae	RCV000179775	SCV001212559	pathogenic	Maple syrup urine disease	2024-01-13	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 290 of the BCKDHA protein (p.Gly290Arg). This variant is present in population databases (rs137852871, gnomAD 0.006%). This missense change has been observed in individual(s) with maple syrup urine disease (PMID: 7883996, 29306928). This variant is also known as G245R. ClinVar contains an entry for this variant (Variation ID: 2377). 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: 7883996). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001175041	SCV001338564	pathogenic	Maple syrup urine disease type 1A	2020-04-03	criteria provided, single submitter	clinical testing	Variant summary: BCKDHA c.868G>A (p.Gly290Arg) results in a non-conservative amino acid change located in the Dehydrogenase E1 component domain (IPR001017) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251368 control chromosomes (gnomAD). c.868G>A has been reported in the literature in multiple homozygous individuals affected with intermediate severity Maple Syrup Urine Disease Type 1A (Chuang_1995, Henneke_2003, Gupta_2015). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant results in slow assembly kinetics with 2-5% residual activities that is consistent with the reported intermediate phenotype (Chuang_1995, Wynn_1998, Henneke_2003). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both of them classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genome-Nilou Lab	RCV000179775	SCV002033484	pathogenic	Maple syrup urine disease	2021-11-07	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000179775	SCV004215886	pathogenic	Maple syrup urine disease	2023-08-28	criteria provided, single submitter	clinical testing
OMIM	RCV000179775	SCV000022633	pathogenic	Maple syrup urine disease	1998-05-22	no assertion criteria provided	literature only
Natera, Inc.	RCV001175041	SCV002088160	pathogenic	Maple syrup urine disease type 1A	2021-02-05	no assertion criteria provided	clinical testing