ClinVar Miner

Submissions for variant NM_003172.4(SURF1):c.833+1G>C

dbSNP: rs782609482
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002240096 SCV002511660 likely pathogenic Leigh syndrome 2022-04-14 criteria provided, single submitter clinical testing Variant summary: SURF1 c.833+1G>C 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: four predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 246384 control chromosomes (gnomAD). To our knowledge, no occurrence of c.833+1G>C in individuals affected with Leigh Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Another variant affecting the same nucleotide (c.833+1G>A) is classified as pathogenic by our laboratory. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV002240096 SCV004465113 pathogenic Leigh syndrome 2023-11-10 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 8 of the SURF1 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with Leigh syndrome (PMID: 22488715). ClinVar contains an entry for this variant (Variation ID: 1683295). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the SURF1 protein in which other variant(s) (p.Ser282Cysfs*9) have been determined to be pathogenic (PMID: 9837813, 16326995, 18583168, 22488715, 23829769). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

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