ClinVar Miner

Submissions for variant NM_001458.4(FLNC):c.1166G>A (p.Gly389Asp) (rs763039506)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000487193 SCV000565014 uncertain significance not provided 2018-09-25 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the FLNC gene. The G389D variant has not been published as pathogenic or been reported as benign to our knowledge. G389D is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. However, the G389D variant is observed in 16/25,784 (0.06%) alleles from individuals of European (Finnish) ancestry and 15/126,668 (0.01%) alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). Furthermore, this variant lacks observation in a significant number of affected individuals, segregation data, and functional evidence, which would further clarify its pathogenicity.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Invitae RCV000649173 SCV000770998 uncertain significance Myofibrillar myopathy, filamin C-related; Myopathy, distal, 4; Cardiomyopathy, familial hypertrophic, 26; Dilated Cardiomyopathy, Dominant 2018-08-07 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 389 of the FLNC protein (p.Gly389Asp). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is present in population databases (rs763039506, ExAC 0.05%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with FLNC-related disease. ClinVar contains an entry for this variant (Variation ID: 418214). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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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