Submissions for variant NM_017777.4(MKS1):c.1408-34_1408-6del

dbSNP: rs386834043

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000168467	SCV000219167	pathogenic	Familial aplasia of the vermis; Meckel-Gruber syndrome	2024-01-24	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. RNA analysis indicates that this variant induces altered splicing and likely disrupts the C-terminus of the protein. This variant is present in population databases (rs749737706, gnomAD 0.7%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individual(s) with Meckel-Gruber syndrome (PMID: 16415886, 17377820, 17397051, 17437276, 17935508). It is commonly reported in individuals of Finnish ancestry (PMID: 23351400). ClinVar contains an entry for this variant (Variation ID: 188400). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 16 and introduces a new termination codon (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	Familial aplasia of the vermis	2016-06-19	criteria provided, single submitter	clinical testing
GeneDx	RCV000273342	SCV000330065	pathogenic	not provided	2022-05-03	criteria provided, single submitter	clinical testing	Described as a founder mutation in the Finnish population and many other European populations (Kyttala et al., 2006; Frank et al., 2007); Published functional studies demonstrate abnormal gene splicing (Kyttala et al., 2006); In silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 17377820, 23351400, 17437276, 17935508, 16415886, 17397051, 27377014, 29096034)
CeGaT Center for Human Genetics Tuebingen	RCV000273342	SCV000493247	pathogenic	not provided	2024-03-01	criteria provided, single submitter	clinical testing	MKS1: PM3:Very Strong, PM2, PP3, PS3:Supporting
Eurofins Ntd Llc (ga)	RCV000273342	SCV000700971	pathogenic	not provided	2017-04-11	criteria provided, single submitter	clinical testing
Myriad Genetics, 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
Revvity Omics, Revvity	RCV000273342	SCV002024355	pathogenic	not provided	2023-06-16	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000273342	SCV002070502	pathogenic	not provided	2019-05-29	criteria provided, single submitter	clinical testing	DNA sequence analysis of the MKS1 gene demonstrated a 29 bp-deletion in intron 15, c.1408-34_1408-6del. This intronic change is a founder mutation in the Finnish population and a known cause of Meckel-Gruber syndrome. It has been reported in the homozygous and compound heterozygous state in multiple affected individuals (PMIDs: 16415886, 17935508, 17397051). Functional studies in an affected individual's fibroblasts have demonstrated that this variant disrupts mRNA splicing leading to a premature stop codon and a truncated or absent protein (PMID: 16415886).
Ambry Genetics	RCV002515190	SCV003547042	pathogenic	Inborn genetic diseases	2022-01-26	criteria provided, single submitter	clinical testing	The c.1408-34_1408-6del29 alteration is located in intron 15 of the MKS1 gene. This alteration consists of a deletion of 29 nucleotides at nucleotide position c.1408-34 to c.1408-6. This mutation has been identified in the homozygous state in multiple Meckel syndrome families and is considered a founder mutation in the Finnish population (Kyttälä, 2006). It has also been reported in several other individuals in the homozygous or compound heterozygous state with Meckel syndrome or a MKS1-related ciliopathy (Consugar, 2007; Szymanska, 2012; Bader, 2016). Analysis of fibroblasts from an individual homozygous for this mutation demonstrated aberrant splicing (Kyttälä, 2006). Based on the available evidence, this alteration is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000210823	SCV003845047	pathogenic	Meckel syndrome, type 1	2023-02-20	criteria provided, single submitter	clinical testing	Variant summary: MKS1 c.1408-34_1408-6del29 alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 3 prime acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0011 in 246468 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MKS1 causing Meckel Syndrome Type 1, allowing no conclusion about variant significance. c.1408-34_1408-6del29 has been reported in the literature in individuals affected with Meckel Syndrome Type 1. These data indicate that the variant is likely to be associated with disease. Twelve clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (pathogenic n=11, VUS n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Human Genetics, University Hospital of Duesseldorf	RCV000210823	SCV004171177	pathogenic	Meckel syndrome, type 1		criteria provided, single submitter	not provided
Baylor Genetics	RCV003474892	SCV004194914	pathogenic	Bardet-Biedl syndrome 13	2024-03-30	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
PreventionGenetics, part of Exact Sciences	RCV004528921	SCV004105551	pathogenic	MKS1-related disorder	2024-06-14	no assertion criteria provided	clinical testing	The MKS1 c.1408-34_1408-6del29 variant is predicted to result in an intronic deletion. This deletion has been shown to disrupt splicing of MKS1 and cause Meckel-Gruber syndrome in multiple unrelated individuals when found in the homozygous or compound heterozygous states (reported as IVS15-7_35del in Table 1, Kyttala et al. 2006. PubMed ID: 16415886; reported as c.1408-35_1408-7del29, Szymanska et al. 2012. PubMed ID: 23351400). This variant is reported in 0.70% of alleles in individuals of European (Finnish) descent in gnomAD. In ClinVar, this variant is reported as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/188400/). This variant is interpreted as pathogenic.