ClinVar Miner

Submissions for variant NM_000709.4(BCKDHA):c.889C>T (p.Arg297Cys)

gnomAD frequency: 0.00002  dbSNP: rs145901144
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000671303 SCV000796264 uncertain significance Maple syrup urine disease 2017-12-06 criteria provided, single submitter clinical testing
Invitae RCV000671303 SCV001576577 pathogenic Maple syrup urine disease 2023-06-05 criteria provided, single submitter clinical testing 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. This variant disrupts the p.Arg297 amino acid residue in BCKDHA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10745006, 17922217, 29306928). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 555477). This missense change has been observed in individuals with maple syrup urine disease (PMID: 16786533, 28830848). This variant is present in population databases (rs145901144, gnomAD 0.007%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 297 of the BCKDHA protein (p.Arg297Cys).
Genome-Nilou Lab RCV000671303 SCV002032918 likely pathogenic Maple syrup urine disease 2021-11-07 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003323673 SCV004028811 uncertain significance not specified 2023-07-05 criteria provided, single submitter clinical testing Variant summary: BCKDHA c.889C>T (p.Arg297Cys) results in a non-conservative amino acid change located in the Dehydrogenase, E1 component (IPR001017) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251450 control chromosomes (gnomAD). c.889C>T has been reported in the literature in individuals affected with Maple Syrup Urine Disease (examples: Rodriguez-Pombo_2006 and Cheng_2017). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28830848, 16786533). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=1) and pathogenic/likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Baylor Genetics RCV000671303 SCV004215891 likely pathogenic Maple syrup urine disease 2023-08-09 criteria provided, single submitter clinical testing

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