ClinVar Genomic variation as it relates to human health

The BCKDHB c.970C>T (p.Arg324Ter) stop-gained variant is reported in five studies in a total of six individuals with maple syrup urine disease, including one who was homozygous for the variant and five, including a sibling pair, who were compound heterozygous (McConnell et al. 1997; Puckett et al. 2010; Bashyam et al. 2012; Narayanan et al. 2013; Couce et al. 2015). The p.Arg324Ter variant was absent from 100 controls and is reported at a frequency of 0.00044 in the Latino population of the Exome Aggregation Consortium. Functional studies in patient lymphoblasts carrying the p.Arg324Ter variant demonstrate that variant BCKD enzyme activity is <1% of that of the control enzyme activity. Western blotting experiments showed that the variant resulted in a truncated protein which was not detected in the mitochondria suggesting that the missing amino acids may be necessary for tetramer formation (McConnell et al. 1997; Nellis et al. 2003). Based on the evidence and the potential impact of stop-gained variants, the p.Arg324Ter variant is classified as pathogenic for maple syrup urine disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID 9375800, 26232051, 25525159]

Variant summary: BCKDHB c.970C>T (p.Arg324X) 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 6.1e-05 in 245644 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in BCKDHB causing Maple Syrup Urine Disease Type 1B (6.1e-05 vs 0.0015), allowing no conclusion about variant significance. c.970C>T has been reported in the literature in multiple individuals affected with Maple Syrup Urine Disease Type 1B (Bashyam_2012, Couce_2015, McConnell_1997, Narayanan_2013, Puckett_2010). 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 (McConnell_1997). Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

This sequence change creates a premature translational stop signal (p.Arg324*) 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 (rs398124603, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with maple syrup urine disease (PMID: 20307994, 22593002, 24772966, 26232051). This variant is also known as p.Arg274*. ClinVar contains an entry for this variant (Variation ID: 96621). For these reasons, this variant has been classified as Pathogenic.