Submissions for variant NM_183050.4(BCKDHB):c.403G>A (p.Gly135Arg)

dbSNP: rs751953459

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589594	SCV000700010	likely pathogenic	Maple syrup urine disease type 1B	2023-04-12	criteria provided, single submitter	clinical testing	Variant summary: BCKDHB c.403G>A (p.Gly135Arg) results in a non-conservative amino acid change located in the Transketolase-like, pyrimidine-binding domain (IPR005475) 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 4e-06 in 251200 control chromosomes (gnomAD). c.403G>A has been reported in the literature in individuals affected with Maple Syrup Urine Disease Type 1B (Henneke_2003, Rodriguez-Pombo_2006, Narayanan_2013). These data indicate that the variant is likely to be associated with disease. Two studies have measured the BCKD enzyme activity in patients with the variant and found it to be <5% of the normal levels (Henneke_2003; Rodriguez-Pombo_2006). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified it as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Eurofins Ntd Llc (ga)	RCV000732154	SCV000860064	pathogenic	not provided	2018-03-21	criteria provided, single submitter	clinical testing
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001814191	SCV001755229	pathogenic	Abnormality of metabolism/homeostasis	2021-07-10	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001796129	SCV002033144	likely pathogenic	Maple syrup urine disease	2021-11-07	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001796129	SCV002807584	likely pathogenic	Maple syrup urine disease	2022-04-05	criteria provided, single submitter	clinical testing
Invitae	RCV001796129	SCV003439997	pathogenic	Maple syrup urine disease	2023-04-06	criteria provided, single submitter	clinical testing	This variant is present in population databases (rs751953459, gnomAD 0.0009%). ClinVar contains an entry for this variant (Variation ID: 496569). This missense change has been observed in individual(s) with maple syrup urine disease (PMID: 14517957, 16786533, 24772966). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 135 of the BCKDHB protein (p.Gly135Arg). For these reasons, this variant has been classified as Pathogenic. 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 BCKDHB protein function.
GeneDx	RCV000732154	SCV003915176	likely pathogenic	not provided	2022-10-10	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24772966, 16786533, 33996492, 28612395, 14517957)
Baylor Genetics	RCV001796129	SCV004215951	pathogenic	Maple syrup urine disease	2023-09-24	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000589594	SCV002077433	likely pathogenic	Maple syrup urine disease type 1B	2020-12-16	no assertion criteria provided	clinical testing