Submissions for variant NM_183050.4(BCKDHB):c.853C>T (p.Arg285Ter)

gnomAD frequency: 0.00015  dbSNP: rs398124598

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169304	SCV000220624	likely pathogenic	Maple syrup urine disease	2014-08-22	criteria provided, single submitter	literature only
Eurofins Ntd Llc (ga)	RCV000790747	SCV000232805	pathogenic	not provided	2013-08-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000169304	SCV000952978	pathogenic	Maple syrup urine disease	2024-04-02	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg285*) in the BCKDHB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BCKDHB are known to be pathogenic (PMID: 16786533, 22593002). This variant is present in population databases (rs398124598, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with maple syrup urine disease (PMID: 14517957, 24772966, 25333063). ClinVar contains an entry for this variant (Variation ID: 96615). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193356	SCV001362116	pathogenic	Maple syrup urine disease type 1B	2019-01-21	criteria provided, single submitter	clinical testing	Variant summary: The variant, BCKDHB c.853C>T (p.Arg285X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4.5e-05 in 245582 control chromosomes (gnomAD and publication). This frequency is not significantly higher than expected for a pathogenic variant in BCKDHB causing Maple Syrup Urine Disease Type 1B (4.5e-05 vs 0.0015), allowing no conclusion about variant significance. The variant, c.853C>T has been reported in the literature in multiple individuals affected with Maple Syrup Urine Disease Type 1B (Imtiaz_2017, Bashyam_2012, Quental_2008, Gorzelany_2009, Henneke_2003, Rodriguez-Pombo_2006), which one individual was reported to have <10% normal activity (Rodriguez-Pombo_2006). These data indicate that the variant is very likely to be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Centre for Inherited Metabolic Diseases, Karolinska University Hospital	RCV000169304	SCV001571371	pathogenic	Maple syrup urine disease	2021-04-13	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000169304	SCV002033160	pathogenic	Maple syrup urine disease	2021-11-07	criteria provided, single submitter	clinical testing
National Newborn Screening Laboratory, Hospital Nacional de Niños	RCV000169304	SCV002097374	pathogenic	Maple syrup urine disease		criteria provided, single submitter	clinical testing	This is a null variant in a gene where the loss of function is a known disease mechanism, resulting in a truncated protein by creating a premature stop codon. This variant is present in population databases in low frequency (gnomAD exomes: 0,00004, ExAC: 0,000008). It has been published in the literature associated with individuals with MSUD (PMID:14517957, 16786533, 34556729).
3billion, Medical Genetics	RCV000169304	SCV002572541	pathogenic	Maple syrup urine disease	2022-09-01	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). This stop-gained (nonsense) variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The homozygous variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000096615/ PMID: 14517957). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Baylor Genetics	RCV004566970	SCV004215946	pathogenic	Maple syrup urine disease type 1A	2024-03-09	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001193356	SCV002079877	pathogenic	Maple syrup urine disease type 1B	2020-11-02	no assertion criteria provided	clinical testing
Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)	RCV000169304	SCV003927932	pathogenic	Maple syrup urine disease	2023-04-01	no assertion criteria provided	clinical testing