ClinVar Genomic variation as it relates to human health

The c.117dupC pathogenic variant in the the BCKDHA gene has previously reported been reported in association with maple syrup urine disease (Jacinta et al., 1994; Fernández-Guerra et al., 2014). The duplication causes a frameshift starting with codon Arginine 40, changes this amino acid to a Glutamine residue and creates a premature Stop codon at position 11 of the new reading frame, denoted p.Arg40GlnfsX11. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay

Variant summary: BCKDHA c.117dupC (p.Arg40GlnfsX11) 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 2.4e-05 in 250846 control chromosomes (gnomAD). c.117dupC has been reported in the literature in individuals affected with Maple syrup urine disease (Chuang _1994, Rodriguez-Pombo_2006). In addition, Rodriguez-Pombo_2006 reports variant effect results in <10% of normal BCKD activity. These data indicate that the variant may be associated with disease.Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

This sequence change creates a premature translational stop signal (p.Arg40Glnfs*11) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with maple syrup urine disease (PMID: 8037208, 16786533). ClinVar contains an entry for this variant (Variation ID: 166741). For these reasons, this variant has been classified as Pathogenic.

A Heterozygous Frameshift, Splice site region variant c.110_111insC in Exon 2 of the BCKDHA gene that results in the amino acid substitution p.Arg40fs*11 was identified. The observed variant has a maximum allele frequency of 0.00002% in gnomAD exomes and genomes, respectively. This variant has been reported as pathogenic in ClinVar (variant ID: 166741) with 2 stars, criteria. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. This variant has previously been reported for MSUD in patients by Rodríguez-Pombo P, et, al., 2006. Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.

The c.117dupC (p.R40Qfs*11) alteration, located in exon 2 (coding exon 2) of the BCKDHA gene, consists of a duplication of C at position 117, causing a translational frameshift with a predicted alternate stop codon after 11 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from the Genome Aggregation Database (gnomAD) database, the BCKDHA c.117dupC alteration was observed in 0.0024% (6/250,846) of total alleles studied, with a frequency of 0.0044% (5/113,326) in the European (non-Finnish) subpopulation. This alteration has been identified with a second alteration in BCKDHA in several unrelated patients with intermediate or classic maple syrup urine disease (Chuang, 1994, Fernandez-Guerra, 2014, Zhang, 2019). Based on the available evidence, this alteration is classified as pathogenic.