ClinVar Miner

Submissions for variant NM_194454.3(KRIT1):c.879_880delinsTT (p.Arg294Ter)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Clinical Genomics Laboratory, Washington University in St. Louis RCV004560374 SCV005047057 pathogenic Cerebral cavernous malformation 2024-04-10 criteria provided, single submitter clinical testing A KRIT1 c.879_880delinsTT (p.Arg294*) variant was identified at an allelic fraction consistent with somatic origin. This dinucleotide substitution leads to a premature termination codon, which is predicted to lead to nonsense mediated decay. This variant, to our knowledge, has not been reported in the individuals with vascular malformations in the medical literature. Another variant (c.880C>T, p.Arg294*), that also results in a premature termination codon, has been identified as a germline variant in at least two individuals with cerebral cavernous malformation (Riant F et al., PMID: 23595507; Nardella G et al., PMID: 30161288) and has been reported in the ClinVar database as a germline pathogenic variant by three submitters (ClinVar ID: 590759). The KRIT1 c.879_880delinsTT (p.Arg294*) variant is absent from the general population (gnomAD v.4.0.0), indicating it is not a common variant. Based on an internally-developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868), the KRIT1 c.879_880delinsTT (p.Arg294*) variant is classified as pathogenic.

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