ClinVar Miner

Submissions for variant NM_017777.4(MKS1):c.858+1G>A

dbSNP: rs756102768
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000672305 SCV000797402 likely pathogenic Bardet-Biedl syndrome 13; Meckel syndrome, type 1; Joubert syndrome 28 2018-01-30 criteria provided, single submitter clinical testing
Molecular Genetics, Royal Melbourne Hospital RCV002225110 SCV002503722 uncertain significance Joubert syndrome 28 2023-03-30 criteria provided, single submitter clinical testing This sequence change affects the canonical donor splice site in intron 18 of MKS1. It is expected to disrupt RNA splicing and likely results in cryptic donor site usage leading to intron inclusion of 21 bp (SpliceAI). The predicted effect is an in-frame insertion of 7 amino acids in a region with no known functional domain. This has not been confirmed using RNA studies. The variant is present in a single individual in a large population cohort (rs756102768, 1/249,584 alleles, 0 homozygotes in gnomAD v2.1), and has been reported as likely pathogenic previously (ClinVar). The variant has not been reported in the relevant medical literature. Based on the classification scheme RMH Modified ACMG Guidelines v1.3.0, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PVS1_Moderate, PM2_Supporting.
Labcorp Genetics (formerly Invitae), Labcorp RCV003767996 SCV004588224 likely pathogenic Familial aplasia of the vermis; Meckel-Gruber syndrome 2023-10-22 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 8 of the MKS1 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 MKS1 are known to be pathogenic (PMID: 19466712, 24886560, 26490104). This variant is present in population databases (rs756102768, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with MKS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 556312). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.