ClinVar Genomic variation as it relates to human health

This variant has been previously reported in patients with Maple Syrup Urine Disease (PMID: 14517957, 17922217, 26257134, 21098507). Functional studies showed that BCKDC enzyme activity measured on skin fibroblasts from patients that were homozygous for this variant was significantly reduced (0.26% of normal control) (PMID: 21098507). The c.1234G>A (p.Val412Met) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.003% (1/30938) and thus is presumed to be rare. This variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.1234G>A (p.Val412Met) variant is classified as pathogenic.

Variant summary: BCKDHA c.1234G>A (p.Val412Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249364 control chromosomes. c.1234G>A has been reported in the literature in individuals affected with Maple Syrup Urine Disease (example, Henneke_2003, Flaschker_2007, Brunetti-Pierri_2011, Gupta_2015). These data indicate that the variant is very likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (example, Flaschker_2007, Brunetti-Pierri_2011). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

This is a missense variant located within exon 9 and generates a change from the amino acid Valine to a Methionine in position 412. It is not present in population databases (GnomAD exomes; GnomAD genomes). This variant is associated in one publication with an individual with MSUD phenotype (PMID: 14517957). It was found in a compound heterozygous state in a patient with biochemical analysis supporting the diagnosis of MSUD (NBS dried blood sample: Xle: 2045umol/L, Val: 554umol/L. Pre-treatment plasma aminogram: Leu: 2747umol/L, Val: 788umol/L, Ile: 491umol/L).

The c.1234G>A (p.V412M) alteration is located in exon 9 (coding exon 9) of the BCKDHA gene. This alteration results from a G to A substitution at nucleotide position 1234, causing the valine (V) at amino acid position 412 to be replaced by a methionine (M). Based on data from gnomAD, the A allele has an overall frequency of <0.01% (1/31384) total alleles studied. The highest observed frequency was 0.01% (1/15416) of European (non-Finnish) alleles. This alteration has been detected in the homozygous state and as compound heterozygous in trans with other pathogenic BCKDHA alterations in multiple unrelated individuals with BCKDHA-related maple syrup urine disease (Henneke, 2003; Flaschker, 2007; Brunett-Pierri, 2011; Gupta, 2015; Strauss, 2020). This amino acid position is well conserved in available vertebrate species. Based on internal structural analysis, V412M is moderately destabilizing (Li, 2007; Machius, 2006). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 412 of the BCKDHA protein (p.Val412Met). This variant is present in population databases (rs398123490, gnomAD 0.007%). This missense change has been observed in individual(s) with maple syrup urine disease (PMID: 17922217, 21098507, 26257134). ClinVar contains an entry for this variant (Variation ID: 93344). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BCKDHA protein function. For these reasons, this variant has been classified as Pathogenic.