Submissions for variant NM_001918.5(DBT):c.1385G>C (p.Arg462Pro)

dbSNP: rs750594890

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001918341	SCV002181942	pathogenic	Maple syrup urine disease	2023-07-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 462 of the DBT protein (p.Arg462Pro). For these reasons, this variant has been classified as 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: 1407245). This missense change has been observed in individual(s) with maple syrup urine disease (PMID: 11112664, 26232051). This variant is present in population databases (rs750594890, gnomAD 0.01%).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001918341	SCV004038310	pathogenic	Maple syrup urine disease	2023-08-07	criteria provided, single submitter	clinical testing	Variant summary: DBT c.1385G>C (p.Arg462Pro) 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 2e-05 in 251146 control chromosomes. c.1385G>C has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Maple Syrup Urine Disease (e.g., Rodriguez-Pombo_2006, Nellis_2001). These data indicate that the variant is very likely to 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: 11112664, 16786533). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genome-Nilou Lab	RCV001918341	SCV004050137	pathogenic	Maple syrup urine disease	2023-04-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001918341	SCV004190851	pathogenic	Maple syrup urine disease	2023-09-19	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005050453	SCV005683827	pathogenic	Maple syrup urine disease type 2	2024-06-06	criteria provided, single submitter	clinical testing