ClinVar Miner

Submissions for variant NM_194456.1(KRIT1):c.1A>G (p.Met1Val) (rs1554539120)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000536000 SCV000644717 likely pathogenic Cerebral cavernous malformation 2016-08-24 criteria provided, single submitter clinical testing This sequence change affects the initiator methionine of the KRIT1 mRNA. The next in-frame methionine is located at c.280 (p.Met94). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a KRIT1-related disease. This variant has been observed in an individual with features of cerebral cavernous malformations (Invitae database), which suggests that this variant may contribute to disease. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this is a novel variant that affects the initiator codon of KRIT1, and has been observed in an affected individual. This evidence strongly suggests that the variant is pathogenic, but the available data is currently insufficient to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneDx RCV000578776 SCV000680536 pathogenic not provided 2016-11-01 criteria provided, single submitter clinical testing The c.1 A>G pathogenic variant in the KRIT1 gene alters the initiator Methionine codon, and the resultant protein would be described as “p.Met1?” using a question mark to signify that it is not known if the loss of Met1 means that all protein translation is completely prevented or if an abnormal protein is produced using an alternate Met. This variant has not been reported previously to our knowledge.. Furthermore, the NHLBI ESP Exome Variant Server reports c.1 A>G was not observed in approximately 6,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations.
PreventionGenetics,PreventionGenetics RCV000578776 SCV000853018 likely pathogenic not provided 2017-02-15 criteria provided, single submitter clinical testing

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