ClinVar Miner

Submissions for variant NM_001165927.1(MKS1):c.1420_1423dup (p.Thr475fs) (rs386834044)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000230084 SCV000290334 pathogenic Joubert syndrome 2016-02-08 criteria provided, single submitter clinical testing This sequence change inserts 4 nucleotides in exon 16 of the MKS1 mRNA (c.1450_1453dupGGCA), causing a frameshift at codon 485. This creates a premature translational stop signal (p.Thr485Argfs*107) and is expected to result in an absent or disrupted protein product. Truncating variants in MKS1 are known to be pathogenic. This particular truncation has been reported in the homozygous state from an individual affected with Meckel Gruber syndrome in the literature (PMID: 17397051, 17185389). This variant is also known as c.1448_1451dupCAGG; p.G484fsX108 in the literature. For these reasons, this variant has been classified as Pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000340753 SCV000404278 likely pathogenic MKS1-Related Disorders 2017-04-27 criteria provided, single submitter clinical testing The MKS1 c.1450_1453dupGGCA (p.Thr485ArgfsTer107) variant, also known as c.1448_1451dupCAGG, results in a frameshift and is predicted to cause an elongation of the protein. Across a selection of available literature, the p.Thr485ArgfsTer107 variant was identified in a homozygous state in four individuals with Meckel syndrome from consanguineous families of Pakistani origin (Dawe et al. 2007; Khaddour et al. 2007; Szymanska et al. 2012). The p.Thr485ArgfsTer107 variant has not been reported in any cases of Bardet-Biedl syndrome. The variant was absent from 96 healthy controls but is reported at a frequency of 0.00067 in the South Asian population of the Exome Aggregation Consortium. Dawe et al. (2007) conducted immunohistochemistry staining in kidney tissue from an affected individual carrying the p.Thr485ArgfsTer107 variant and demonstrated a lack of MKS1 protein compared to age-matched control tissue. Based on the evidence from the literature and potential impact of frameshift variants, the p.Thr485ArgfsTer107 variant is classified as likely pathogenic for MKS1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV001063563 SCV001228414 pathogenic Joubert syndrome; Meckel-Gruber syndrome 2019-12-23 criteria provided, single submitter clinical testing This sequence change inserts 4 nucleotides in exon 16 of the MKS1 mRNA (c.1450_1453dupGGCA), causing a frameshift at codon 485. This creates a premature translational stop signal (p.Thr485Argfs*107) and is expected to result in an absent or disrupted protein product. Truncating variants in MKS1 are known to be pathogenic. This particular truncation has been reported in the homozygous state from an individual affected with Meckel Gruber syndrome in the literature (PMID: 17397051, 17185389). This variant is also known as c.1448_1451dupCAGG; p.G484fsX108 in the literature. For these reasons, this variant has been classified as Pathogenic.
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) RCV000050030 SCV000082439 probable-pathogenic Meckel syndrome type 1 no assertion criteria provided not provided Converted during submission to Likely pathogenic.
Counsyl RCV000050030 SCV001132431 likely pathogenic Meckel syndrome type 1 2016-12-05 no assertion criteria provided clinical testing
Counsyl RCV000984282 SCV001132432 likely pathogenic Bardet-Biedl syndrome 13 2016-12-05 no assertion criteria provided clinical testing
Counsyl RCV000984283 SCV001132433 likely pathogenic Joubert syndrome 28 2016-12-05 no assertion criteria provided clinical testing

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