ClinVar Genomic variation as it relates to human health

Variant summary: BCKDHA c.859C>T (p.Arg287X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251376 control chromosomes. c.859C>T has been reported in the literature in multiple individuals affected with Maple Syrup Urine Disease and subsequently cited by others (example, Chinsky_1997, Henneke_2003, Feier_2016, Scaini_2018, Zlotogora_2020). 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 BCKD enzyme activity on patient fibroblasts (Henneke_2003). 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.

This variant, also referred to historically as p.Arg242*, has been reported in the literature in at least 5 individuals with maple syrup urine disease, including in both the homozygous and compound heterozygous states (Chinsky 1997 PMID: 10694918; Henneke 2003 PMID: 14517957; Feier 2016 PMID: 26786177; Scaini 2018 PMID: 29740775; Khalifa 2020 PMID: 32812330). This variant is present in gnomAD (Highest reported MAF: 0.01% [4/41408]; https://gnomad.broadinstitute.org/variant/19-41422634-C-T?dataset=gnomad_r3); please note, disease-causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. It is also present in ClinVar (Variation ID: 553989). This variant is predicted to cause a stopgain at this codon, resulting in protein truncation or loss of allelic expression through nonsense-mediated mRNA decay; biallelic loss of function is an established mechanism of disease for this gene (Blackburn 2017 PMID: 28919799). Patient-derived fibroblasts with this variant in the homozygous state exhibited BCKD enzyme activity of approximately 3% compared to the wild-type enzyme (Henneke 2003 PMID: 14517957). In summary, this variant is classified as pathogenic.

This sequence change creates a premature translational stop signal (p.Arg287*) 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 (rs764247545, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with maple syrup urine disease (PMID: 10694918, 14517957, 19480318, 29740775, 32812330). This variant is also known as R242X. ClinVar contains an entry for this variant (Variation ID: 553989). For these reasons, this variant has been classified as Pathogenic.