Submissions for variant NM_000108.5(DLD):c.1382G>A (p.Gly461Glu)

gnomAD frequency: 0.00004  dbSNP: rs757275923

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000185861	SCV000238812	uncertain significance	not provided	2017-05-16	criteria provided, single submitter	clinical testing	A G461E missense change has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. G461E is a non-conservative amino acid substitution as a small, uncharged Glycine residue is replaced with a large, negatively charged Glutamic acid residue. The variant occurs in the pyridine nucleotide-disulphide oxidoreductase dimerisation domain of the DLD protein at a position that is highly conserved across species. Multiple in silico algorithms predict that G461E is damaging to the structure/function of the DLD protein. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001277173	SCV002600622	likely pathogenic	Pyruvate dehydrogenase E3 deficiency	2022-10-21	criteria provided, single submitter	clinical testing	Variant summary: DLD c.1382G>A (p.Gly461Glu) results in a non-conservative amino acid change located in the Pyridine nucleotide-disulphide oxidoreductase, dimerisation domain (IPR004099) of the encoded protein sequence (Szabo_2019). 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 4.4e-05 in 251238 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in DLD causing Dihydrolipoamide Dehydrogenase Deficiency (MSUD Type 3) (4.4e-05 vs 0.005), allowing no conclusion about variant significance. c.1382G>A has been reported in the literature as a biallelic compound heterozygous genotype in at-least one individual affected with features of Dihydrolipoamide Dehydrogenase Deficiency (example, Carrozzo_2014). These data do not allow any conclusion about variant significance. To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001277173	SCV003522965	uncertain significance	Pyruvate dehydrogenase E3 deficiency	2022-08-22	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 461 of the DLD protein (p.Gly461Glu). This variant is present in population databases (rs757275923, gnomAD 0.02%). This missense change has been observed in individual(s) with DLD deficiency (PMID: 25251739). 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: 203685). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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.
Baylor Genetics	RCV001277173	SCV004193951	likely pathogenic	Pyruvate dehydrogenase E3 deficiency	2024-03-26	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000185861	SCV004227062	likely pathogenic	not provided	2023-04-28	criteria provided, single submitter	clinical testing	PP3, PP4, PM2, PM3
Natera, Inc.	RCV001277173	SCV001464060	uncertain significance	Pyruvate dehydrogenase E3 deficiency	2020-09-16	no assertion criteria provided	clinical testing