ClinVar Miner

Submissions for variant NM_001458.4(FLNC):c.3133C>A (p.His1045Asn) (rs201863231)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000497327 SCV000590513 uncertain significance not provided 2017-06-23 criteria provided, single submitter clinical testing The c.3133 C>A variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.3133 C>A variant is observed in 6/63416 (0.01%) alleles from individuals of European background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Multiple in-silico splice prediction models predict that c.3133 C>A creates a cryptic splice donor site which may supplant the natural donor site and lead to abnormal gene splicing. However, in the absence of RNA/functional studies the actual effect of c.3133 C>A on splicing in this individual is unknown. If c.3133 C>A does not alter splicing, it will result in the H1045N missense change. The H1045N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals; however, missense variants in nearby residues have not been reported in the Human Gene Mutation Database in association with FLNC-related disorders (Stenson et al., 2014). In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Invitae RCV000701577 SCV000830384 uncertain significance Myofibrillar myopathy, filamin C-related; Myopathy, distal, 4; Cardiomyopathy, familial hypertrophic, 26; Dilated Cardiomyopathy, Dominant 2018-11-09 criteria provided, single submitter clinical testing This sequence change replaces histidine with asparagine at codon 1045 of the FLNC protein (p.His1045Asn). The histidine residue is moderately conserved and there is a small physicochemical difference between histidine and asparagine. This variant is present in population databases (rs201863231, ExAC 0.02%). This variant has not been reported in the literature in individuals with FLNC-related disease. ClinVar contains an entry for this variant (Variation ID: 432753). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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