Submissions for variant NM_001918.5(DBT):c.1126C>T (p.Arg376Cys)

dbSNP: rs768389398

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000670216	SCV000795046	uncertain significance	Maple syrup urine disease	2017-10-25	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001092053	SCV001248398	pathogenic	not provided	2018-10-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000670216	SCV002033176	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	RCV001797779	SCV002041639	uncertain significance	not specified	2021-11-03	criteria provided, single submitter	clinical testing	Variant summary: DBT c.1126C>T (p.Arg376Cys) results in a non-conservative amino acid change located in the 2-oxoacid dehydrogenase acyltransferase, catalytic domain (IPR001078) 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 1.6e-05 in 251464 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1126C>T has been reported in the literature as a compound heterozygous genotype in at-least one individual affected with Maple Syrup Urine Disease, whose plasma demonstrated a characteristic amino acid profile (elevated Valine, Isoleucine, Leucine and presence of Alloisoleucine) and fibroblasts demonstrated reduced BCKD activity and E2 protein content (example, Brodtkorb_2010). These report(s) do not provide unequivocal conclusions about association of the variant with Maple Syrup Urine Disease. To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, until additional clinical reports supported by functional analysis are identified, the variant was classified as VUS-possibly pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000670216	SCV004291957	likely pathogenic	Maple syrup urine disease	2023-05-22	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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 DBT protein function. ClinVar contains an entry for this variant (Variation ID: 554556). This missense change has been observed in individual(s) with maple syrup urine disease (PMID: 20570198). This variant is present in population databases (rs768389398, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 376 of the DBT protein (p.Arg376Cys).