ClinVar Miner

Submissions for variant NM_001165927.1(MKS1):c.1378-34_1378-6del (rs386834043)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000168467 SCV000219167 pathogenic Joubert syndrome; Meckel-Gruber syndrome 2020-10-30 criteria provided, single submitter clinical testing This sequence change falls in intron 15 of the MKS1 gene. It does not directly change the encoded amino acid sequence of the MKS1 protein, but it affects a nucleotide within the consensus splice site of the intron. RNA analysis indicates that this variant induces altered splicing and likely disrupts the C-terminus of the protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in individual(s) with Meckel-Gruber syndrome and recognized as a founder mutation in the Finnish population (PMID: 16415886, 17437276, 17377820, 17935508, 17397051). ClinVar contains an entry for this variant (Variation ID: 188400). Studies have shown that this variant is associated with skipping of exon 16, which introduces a frameshift (PMID: 16415886). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Universitätsklinikum Salzburg,Universitätskinderklinik RCV000491550 SCV000282232 pathogenic Joubert syndrome 2016-06-19 criteria provided, single submitter clinical testing
GeneDx RCV000273342 SCV000330065 pathogenic not provided 2018-06-11 criteria provided, single submitter clinical testing The c.1408-34_1408-6del29 pathogenic variant in the MSK1 gene has been reported previously using alternate nomenclature (IVS15-7_35, c.1408-7_35del) in association with autosomal recessive ciliopathies when present in the homozygous state or when in trans with another disease-causing variant (Kyttala et al., 2006; Khaddour et al., 2007; Frank et al, 2007; Auber et al., 2007). The c.1408-34_1408-6del29 variant is a founder mutation in the Finnish population and many other European populations (Kyttala et al., 2006; Frank et al., 2007). This deletion destroys the natural splice acceptor site in intron 15, and functional studies of this variant have demonstrated abnormal gene splicing (Kyttala et al., 2006). This variant was not observed in approximately 6300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.1408-34_1408-6del29 as a pathogenic variant.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000273342 SCV000493247 uncertain significance not provided 2016-08-01 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000273342 SCV000700971 pathogenic not provided 2017-04-11 criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000210823 SCV001194240 pathogenic Meckel syndrome type 1 2019-12-24 criteria provided, single submitter clinical testing NM_017777.3(MKS1):c.1408-34_1408-6del29 is classified as pathogenic in the context of MKS1-related disorders. Sources cited for classification include the following: PMID 16415886 and 23351400. Classification of NM_017777.3(MKS1):c.1408-34_1408-6del29 is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000984005 SCV001448960 pathogenic Joubert syndrome 28 2018-04-08 criteria provided, single submitter clinical testing
OMIM RCV000210823 SCV000043096 pathogenic Meckel syndrome type 1 2007-11-01 no assertion criteria provided literature only
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) RCV000210823 SCV000082438 pathogenic Meckel syndrome type 1 no assertion criteria provided not provided Converted during submission to Pathogenic.
Counsyl RCV000984005 SCV000795925 pathogenic Joubert syndrome 28 2017-11-29 no assertion criteria provided clinical testing
Natera, Inc. RCV000210823 SCV001455368 pathogenic Meckel syndrome type 1 2020-09-16 no assertion criteria provided clinical testing

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