Submissions for variant NM_001918.5(DBT):c.902G>A (p.Arg301His)

gnomAD frequency: 0.00001  dbSNP: rs770981889

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000503792	SCV000590928	pathogenic	Maple syrup urine disease	2017-06-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000503792	SCV003248306	uncertain significance	Maple syrup urine disease	2021-09-01	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with histidine at codon 301 of the DBT protein (p.Arg301His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs770981889, ExAC 0.006%). This variant has not been reported in the literature in individuals affected with DBT-related conditions. ClinVar contains an entry for this variant (Variation ID: 437447). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant disrupts the p.Arg301 amino acid residue in DBT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20570198, 21098507, 27518768). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003488640	SCV004241123	uncertain significance	not specified	2023-12-15	criteria provided, single submitter	clinical testing	Variant summary: DBT c.902G>A (p.Arg301His) results in a non-conservative amino acid change located in the 2-oxoacid dehydrogenase acyltransferase, catalytic domain (IPR001078) 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 8e-06 in 251460 control chromosomes. 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.902G>A in individuals affected with Maple Syrup Urine Disease and no experimental evidence demonstrating its impact on protein function have been reported. Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as pathogenic, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV004568642	SCV005051741	pathogenic	Maple syrup urine disease type 2	2024-02-01	criteria provided, single submitter	curation