Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001377798 | SCV001575223 | pathogenic | Familial aplasia of the vermis; Meckel-Gruber syndrome | 2022-11-15 | criteria provided, single submitter | clinical testing | This variant is present in population databases (no rsID available, gnomAD no frequency). This sequence change falls in intron 10 of the MKS1 gene. It does not directly change the encoded amino acid sequence of the MKS1 protein. This variant has been observed in individual(s) with clinical features of Joubert syndrome (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 1066722). |
| 3billion | RCV003152763 | SCV003841542 | uncertain significance | Meckel syndrome, type 1 | 2023-02-23 | criteria provided, single submitter | clinical testing | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Intron variant. In silico tools predict the variant to alter splicing and produce an abnormal transcript (SpliceAI: 0.98). The variant has been reported to be associated with MKS1-related disorder (ClinVar ID: VCV001066722). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as VUS according to the recommendation of ACMG/AMP guideline. |
| Broad Center for Mendelian Genomics, |
RCV003225971 | SCV003922329 | uncertain significance | Joubert syndrome 28 | 2023-05-02 | criteria provided, single submitter | curation | The homozygous c.959-5C>A variant in MKS1 was identified by our study in one individual with cardiac anomalies, feeding difficulties, chorioretinal coboloma, polydactyly, syndactyly, hypertonia, abnormal cerebral white matter morphology, cerebellar vermis hypoplasia, fusion of the left and right thalami, hydrocephalus, molar tooth sign on MRI, ventriculomegaly, and respiratory difficulties. The phenotype of this individual homozygous for this variant is highly specific for Joubert syndrome based on the presence of cerebellar vermis hypoplasia and molar tooth sign on MRI (PMID: 35238134). The c.959-5C>A variant in MKS1 has not been previously reported in individuals with Joubert syndrome 28, but has been identified in 0.0015% (1/68032) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs765242131). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 1066722) and has been interpreted as likely pathogenic by Invitae. This variant is located in the 3' splice region. Computational tools predict a splicing impact, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PM3_Supporting, PP3, PP4 (Richards 2015). |