Submissions for variant NM_000709.4(BCKDHA):c.940C>T (p.Arg314Ter)

gnomAD frequency: 0.00001  dbSNP: rs753698250

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	RCV000209887	SCV000240045	pathogenic	Maple syrup urine disease	2011-01-01	criteria provided, single submitter	research
Counsyl	RCV000209887	SCV000796958	pathogenic	Maple syrup urine disease	2018-01-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001194035	SCV001363271	pathogenic	Maple syrup urine disease type 1A	2019-04-01	criteria provided, single submitter	clinical testing	Variant summary: BCKDHA c.940C>T (p.Arg314X) 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 4.1e-06 in 246078 control chromosomes. c.940C>T has been reported in the literature in multiple individuals affected with Maple Syrup Urine Disease Type 1A (Nellis_2003, Rodriguez-Pombo_2006, Gupta_2015, Imtiaz_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Nellis_2003, Rodriguez-Pombo_2006). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000209887	SCV001589684	pathogenic	Maple syrup urine disease	2023-11-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg314*) in the BCKDHA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BCKDHA are known to be pathogenic (PMID: 16786533, 22593002). This variant is present in population databases (rs753698250, gnomAD 0.0009%). This premature translational stop signal has been observed in individuals with BCKDHA-related conditions (PMID: 14567968, 31523617). ClinVar contains an entry for this variant (Variation ID: 224072). For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000209887	SCV002033506	pathogenic	Maple syrup urine disease	2021-11-07	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000209887	SCV004100549	pathogenic	Maple syrup urine disease		criteria provided, single submitter	clinical testing	The stop gained p.R314* in BCKDHA (NM_000709.4) has been reported in multiple affected individuals in literature (Gupta D et al,Imtiaz F et al). It has been submitted to ClinVar as Pathogenic. The p.R314* variant is observed in 1/1,13,634 (0.0009%) alleles from individuals of European (Non-Finnish) background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been reported previously to be disease causing. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV001194035	SCV004215879	pathogenic	Maple syrup urine disease type 1A	2024-02-23	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV001194035	SCV005382519	pathogenic	Maple syrup urine disease type 1A	2023-06-22	criteria provided, single submitter	clinical testing	The observed stop gained c.940C>T(p.Arg314Ter) variant in BCKDHA gene has been reported previously in homozygous or compound heterozygous state in individual(s) affected with Maple syrup urine disease (MSUD) (Imtiaz et al., 2017). This variant is reported with the allele frequency of 0.0004% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Loss of function variants have been previously reported to be disease causing (Bashyam et al., 2012). Computational evidence (MutationTaster - Disease causing automatic) predicts damaging effect on protein structure and function for this variant. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV001194035	SCV005648313	pathogenic	Maple syrup urine disease type 1A	2024-06-12	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV001194035	SCV005871482	pathogenic	Maple syrup urine disease type 1A		criteria provided, single submitter	clinical testing	PM2_Supporting+PVS1+PM3_Supporting+PP4
Natera, Inc.	RCV001194035	SCV002088162	pathogenic	Maple syrup urine disease type 1A	2020-07-02	no assertion criteria provided	clinical testing