Submissions for variant NM_000108.5(DLD):c.875+1G>A

gnomAD frequency: 0.00001  dbSNP: rs1328820332

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000012749	SCV000938780	likely pathogenic	Pyruvate dehydrogenase E3 deficiency	2022-02-16	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 9 of the DLD gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in DLD are known to be pathogenic (PMID: 8968745, 9934985). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 11970). Disruption of this splice site has been observed in individual(s) with dihydrolipoamide dehydrogenase deficiency (PMID: 12925875). This variant is present in population databases (no rsID available, gnomAD 0.03%).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000012749	SCV001737694	pathogenic	Pyruvate dehydrogenase E3 deficiency	2021-05-24	criteria provided, single submitter	clinical testing	Variant summary: DLD c.875+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5 splicing donor site. Experimental evidence supports these predictions indicating that this variant affects splicing leading to a totally unstable mRNA (Grafakou_2003). The variant was absent in 250256 control chromosomes (gnomAD). c.875+1G>A has been reported in the literature in a compound heterozygous individual affected with Dihydrolipoamide Dehydrogenase Deficiency who developed Leigh syndrome (Grafakou_2003). Experimental evidence from muscle tissue of this individual demonstrated considerably decreased E3 and PDHc activities. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV000012749	SCV002020384	pathogenic	Pyruvate dehydrogenase E3 deficiency	2019-02-07	criteria provided, single submitter	clinical testing
OMIM	RCV000012749	SCV000032984	pathogenic	Pyruvate dehydrogenase E3 deficiency	2003-10-01	no assertion criteria provided	literature only