ClinVar Miner

Submissions for variant NM_001458.5(FLNC):c.850+1G>T

dbSNP: rs1808146842
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001976571 SCV002262206 likely pathogenic Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant 2022-04-09 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 4 of the FLNC gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in FLNC are known to be pathogenic (PMID: 27908349). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with FLNC-related conditions. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Servicio Canario de Salud, Hospital Universitario Nuestra Sra. de Candelaria RCV004719214 SCV005324801 likely pathogenic Primary dilated cardiomyopathy 2024-09-20 criteria provided, single submitter clinical testing The c.850+1G>T FLNC variant in heterocigous state has been reported in our laboratory in a 60-year-old female patient with a clinical diagnosis of hypocontractile nondilated cardiomyopathy of the left ventricle. A brother who died of sudden death at 52 years of age. This variant has never been reported FLNC-related patients. This variant was absent from large population studies (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 1479021). In silico analysis (SpliceAI) supports that this variant predicts alteration of the splicing donor site, but this prediction has not been confirmed by functional studies. In summary, the available evidence for c.850+1G>T FLNC variant meets our criteria to be classified as likely pathogenic variant based upon its situation at the canonical splicing site and its low frequency in controls. Therefore, it has been classified as a Variant of Likely Pathogenic.

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