ClinVar Miner

Submissions for variant NM_003850.3(SUCLA2):c.534+1G>A

gnomAD frequency: 0.00001  dbSNP: rs113994161
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000020560 SCV003517009 pathogenic Mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria 2023-11-13 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 4 of the SUCLA2 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 SUCLA2 are known to be pathogenic (PMID: 15877282, 17301081). This variant is present in population databases (rs113994161, gnomAD 0.003%). Disruption of this splice site has been observed in individual(s) with clinical features of mitochondrial DNA depletion syndrome (PMID: 17301081). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5976). Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products (PMID: 17301081). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000020560 SCV004029832 pathogenic Mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria 2023-07-25 criteria provided, single submitter clinical testing Variant summary: SUCLA2 c.534+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. At least one publication reports experimental evidence that this variant affects mRNA splicing, demonstrating that the variant creates multiple abberrant transcripts that are missing exons 2, 3 and some or all of exon 4 (e.g., Carrozzo_2007) The variant allele was found at a frequency of 1.2e-05 in 251194 control chromosomes. c.534+1G>A has been reported in the literature in multiple homozygous individuals affected with Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form With Methylmalonic Aciduria (e.g., Carrozzo_2007) . These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 17301081). 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.
OMIM RCV000020560 SCV000026524 pathogenic Mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria 2007-03-01 no assertion criteria provided literature only
GeneReviews RCV000020560 SCV000041036 not provided Mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria no assertion provided literature only

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