ClinVar Miner

Submissions for variant NM_001458.5(FLNC):c.3790G>T (p.Gly1264Cys)

dbSNP: rs201335143
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001773056 SCV002003768 uncertain significance not provided 2021-04-05 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Invitae RCV001868632 SCV002126505 uncertain significance Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant 2021-06-12 criteria provided, single submitter clinical testing This variant is not present in population databases (ExAC no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with FLNC-related conditions. This sequence change replaces glycine with cysteine at codon 1264 of the FLNC protein (p.Gly1264Cys). The glycine residue is moderately conserved and there is a large physicochemical difference between glycine and cysteine. This variant also falls at the last nucleotide of exon 21, which is part of the consensus splice site for this exon.

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