Submissions for variant NM_001918.5(DBT):c.872G>T (p.Arg291Leu)

dbSNP: rs775808731

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000535685	SCV000627815	pathogenic	Maple syrup urine disease	2023-11-21	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 291 of the DBT protein (p.Arg291Leu). This variant is present in population databases (no rsID available, gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of maple syrup urine disease (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 457147). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000535685	SCV000799158	uncertain significance	Maple syrup urine disease	2018-04-10	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000535685	SCV002033177	uncertain significance	Maple syrup urine disease	2021-11-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001844190	SCV002103657	uncertain significance	not specified	2023-11-15	criteria provided, single submitter	clinical testing	Variant summary: DBT c.872G>T (p.Arg291Leu) results in a non-conservative amino acid change located in the 2-oxoacid dehydrogenase acyltransferase, catalytic domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251456 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.872G>T in individuals affected with Maple Syrup Urine Disease and no experimental evidence demonstrating its impact on protein function have been reported. One clinical lab via ClinVar has reported this variant to be observed in trans with another DBT variant in an individual with biochemical findings that are highly specific for Maple Syrup Urine Disease (Invitae). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as pathogenic (n=1) or uncertain significance (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.