Submissions for variant NM_001931.5(DLAT):c.1303C>T (p.Arg435Ter)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003603410	SCV004388994	pathogenic	Pyruvate dehydrogenase E2 deficiency	2024-10-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg435*) in the DLAT gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DLAT are known to be pathogenic (PMID: 20022530, 23021068). This variant is present in population databases (rs782185799, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with Leigh syndrome (PMID: 35094435). ClinVar contains an entry for this variant (Variation ID: 2793499). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003603410	SCV005422716	pathogenic	Pyruvate dehydrogenase E2 deficiency	2024-10-18	criteria provided, single submitter	clinical testing	Variant summary: DLAT c.1303C>T (p.Arg435X) 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 4e-06 in 251040 control chromosomes. c.1303C>T has been reported in the literature in at least one compound heterozygous individual affected with Leigh syndrome (e.g. Stenton_2022). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 2793499). Based on the evidence outlined above, the variant was classified as pathogenic.