Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Women's Health and Genetics/Laboratory Corporation of America, |
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 |
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. |