ClinVar Miner

Submissions for variant NM_001458.4(FLNC):c.4991C>T (p.Thr1664Met) (rs780829334)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Praxis fuer Humangenetik Tuebingen RCV000585445 SCV000693254 uncertain significance not provided 2017-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000585445 SCV000590283 uncertain significance not provided 2018-09-26 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the FLNC gene. The T1664M variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed in 20/276914 (0.007%) alleles from individuals of multiple ethnic backgrounds in large population cohorts (Lek et al., 2016). However, the T1664M variant 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. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000649125 SCV000770950 uncertain significance Myofibrillar myopathy, filamin C-related; Myopathy, distal, 4; Cardiomyopathy, familial hypertrophic, 26; Dilated Cardiomyopathy, Dominant 2018-11-20 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 1664 of the FLNC protein (p.Thr1664Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs780829334, ExAC 0.02%), 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: 432545). 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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