Submissions for variant NM_001918.5(DBT):c.670G>T (p.Glu224Ter)

gnomAD frequency: 0.00022  dbSNP: rs74103423

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000079951	SCV000231639	pathogenic	not provided	2013-08-23	criteria provided, single submitter	clinical testing
GeneDx	RCV000079951	SCV000680731	pathogenic	not provided	2023-05-23	criteria provided, single submitter	clinical testing	Functional studies demonstrate that cell lines with the E224X variant result in a markedly truncated polypeptide compared with full-length wildtype (Fisher et al., 1993); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 8430702, 25087612, 25525159, 31980395, 32812330, 31589614, 31345219)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000179397	SCV000834968	pathogenic	Maple syrup urine disease	2024-11-05	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu224*) in the DBT gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DBT are known to be pathogenic (PMID: 16579849, 16786533). This variant is present in population databases (rs74103423, gnomAD 0.1%). This premature translational stop signal has been observed in individuals with maple syrup urine disease (PMID: 8430702). ClinVar contains an entry for this variant (Variation ID: 94009). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000179397	SCV000893167	pathogenic	Maple syrup urine disease	2018-10-31	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000179397	SCV002018143	pathogenic	Maple syrup urine disease	2019-10-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000179397	SCV002033193	pathogenic	Maple syrup urine disease	2021-11-07	criteria provided, single submitter	clinical testing
DASA	RCV002298465	SCV002588782	pathogenic	Maple syrup urine disease type 2	2022-11-03	criteria provided, single submitter	clinical testing	The c.670G>T;p.(Glu224*) variant creates a premature translational stop signal in the DBT gene. It is expected to result in an absent or disrupted protein product - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 94009; PMID: 32812330) - PS4. The variant is present at low allele frequencies population databases (rs74103423 – gnomAD 0.0009193%; ABraOM 0.000427 frequency - https://abraom.ib.usp.br/) - PM2_supporting. In summary, the currently available evidence indicates that the variant is pathogenic.
Baylor Genetics	RCV004566954	SCV004190853	pathogenic	Maple syrup urine disease type 1A	2024-03-27	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000179397	SCV004847421	pathogenic	Maple syrup urine disease	2024-01-29	criteria provided, single submitter	clinical testing	The p.Glu224X variant (also described as p.Glu163X as a legacy nomenclature) in DBT has been reported in at least 6 individuals in the homozygous or compound heterozygous state with maple syrup urine disease (MSUD), where BCKD enzyme activity was markedly reduced in at least 3 individuals (Fisher 1993 PMID: 8430702, Khalifa 2020 PMID: 32812330). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 94009) and has been identified in 0.09% (37/41420) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). This nonsense variant leads to a premature termination codon at position 43, which is predicted to lead to a truncated or absent protein. This is corroborated by in vitro functional studies that show a truncated protein in patients with MSUD compared with full-length wildtype (Fisher 1993 PMID: 8430702). Biallelic loss of function of the DBT gene is an established disease mechanism in autosomal recessive MSUD. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive MSUD. ACMG/AMP Criteria applied: PVS1_Moderate, PM3, PS3_Supporting, PP4.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000179397	SCV005204172	pathogenic	Maple syrup urine disease	2024-06-20	criteria provided, single submitter	clinical testing	Variant summary: DBT c.670G>T (p.Glu224X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 6.4e-05 in 251466 control chromosomes. c.670G>T has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Maple Syrup Urine Disease (e.g., Fisher_1993). 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 publication has been ascertained in the context of this evaluation (PMID: 8430702). ClinVar contains an entry for this variant (Variation ID: 94009). Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002298465	SCV005642660	pathogenic	Maple syrup urine disease type 2	2024-04-08	criteria provided, single submitter	clinical testing
Counsyl	RCV000179397	SCV000485927	likely pathogenic	Maple syrup urine disease	2016-11-03	no assertion criteria provided	clinical testing