ClinVar Miner

Submissions for variant NM_017777.4(MKS1):c.417G>A (p.Glu139=) (rs386834048)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
UW Hindbrain Malformation Research Program,University of Washington RCV000201633 SCV000256441 pathogenic Joubert syndrome 2015-02-23 criteria provided, single submitter research
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000341018 SCV000340011 uncertain significance not provided 2016-03-14 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000605128 SCV000731819 likely pathogenic Meckel-Gruber syndrome 2017-07-31 criteria provided, single submitter clinical testing The p.Glu139Glu (NM_017777.3 c.417G>A) variant in MKS1 has been reported in 8 co mpound heterozygous individuals with Meckel syndrome and 1 compound heterozygous individual with Joubert syndrome (Consugar 2007, Khaddour 2007, Frank 2007, Tal lila 2009, Bachmann-Gagescu 2015). This variant is located in the last base of t he exon, which is part of the 5? splice region, and has been demonstrated to imp act splicing in patient cells (Consugar 2007). It has been identified in 31/126, 722 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnom ad.broadinstitute.org; dbSNP rs386834048, rs370514840). Although this variant ha s been seen in the general population, its frequency is low enough to be consist ent with a recessive carrier frequency. Biallelic loss of function of the MKS1 g ene is associated with Meckel syndrome and Joubert syndrome. In summary, the p. Glu139Glu variant is likely pathogenic for Meckel syndrome in an autosomal reces sive manner based on its occurrence in affected individuals and demonstrated imp act on splicing.
Counsyl RCV000666711 SCV000791054 likely pathogenic Bardet-Biedl syndrome 13; Meckel syndrome type 1; Joubert syndrome 28 2017-04-24 criteria provided, single submitter clinical testing
Invitae RCV000694137 SCV000822568 pathogenic Joubert syndrome; Meckel-Gruber syndrome 2020-11-01 criteria provided, single submitter clinical testing This sequence change affects codon 139 of the MKS1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the MKS1 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs386834048, ExAC 0.03%). This variant has been reported to segregate with Meckel syndrome in a single family and has been found in several individuals affected with Meckel syndrome or Joubert syndrome (PMID: 17377820, 17397051, 26092869, 17437276, 26490104, 28497568). ClinVar contains an entry for this variant (Variation ID: 1392). Studies have shown that this variant is associated with skipping of exon 4 but is expected to preserve the integrity of the reading frame (PMID: 17377820). For these reasons, this variant has been classified as Pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000022415 SCV000914777 likely pathogenic Meckel syndrome type 1 2018-10-11 criteria provided, single submitter clinical testing The MKS1 c.417G>A (p.Glu139Glu) variant has been reported in three studies in probands with Meckel syndrome (MKS) in which it is found in a total of four individuals, all in a compound heterozygous state with a second pathogenic variant (Consugar et al. 2007; Khaddour et al. 2007; Frank et al. 2007). The p.Glu139Glu variant was absent from 410 control chromosomes but is reported at a frequency of 0.000394 in the Ashkenazi Jewish population of the Genome Aggregation Database. The p.Glu139Glu variant is a synonymous variant that affects the last nucleotide of exon four and is predicted to destroy the splice donor site. RT-PCR and sequence analysis of proband fibroblasts showed a smaller abnormal band which when sequenced, confirmed that the variant results in skipping of exon 4 (Consugar et al. 2007). Aberrant splicing is a known mechanism in MKS. Based on the evidence, the p.Glu139Glu variant is classified as likely pathogenic for Meckel syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Illumina Clinical Services Laboratory,Illumina RCV001123802 SCV001282669 uncertain significance Bardet-Biedl syndrome 13 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
OMIM RCV000022415 SCV000043100 pathogenic Meckel syndrome type 1 2007-06-01 no assertion criteria provided literature only
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) RCV000022415 SCV000082443 probable-pathogenic Meckel syndrome type 1 no assertion criteria provided not provided Converted during submission to Likely pathogenic.

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