ClinVar Miner

Submissions for variant NM_001458.4(FLNC):c.5208C>A (p.Asp1736Glu) (rs1291689149)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000535487 SCV000651063 uncertain significance Myofibrillar myopathy, filamin C-related; Myopathy, distal, 4; Cardiomyopathy, familial hypertrophic, 26; Dilated Cardiomyopathy, Dominant 2017-07-25 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glutamic acid at codon 1736 of the FLNC protein (p.Asp1736Glu). The aspartic acid residue is moderately conserved and there is a small physicochemical difference between aspartic acid and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with FLNC-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamic acid amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000786135 SCV000924801 uncertain significance not provided 2017-09-11 no assertion criteria provided provider interpretation SCICD classification: variant of uncertain significance based on lack of case data and absence of variant in population databases. We do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Gene-level evidence: Both missense and truncating variants in FLNC have been reported in various cardiomyopathies (Ortiz-Genga et al. 2016; Valdes-Mas et al 2014). Variant type: Missense. Total number of cases (not including our patient): 0 -ClinVar: absent -Case Data: There is no published literature available to review. In silico analysis: Per the test report, "Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamic acid amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain." Conservation data: The aspartic acid at codon 1736 is strongly conserved in mammals, but not completely across species, as are neighboring amino acids. Other variants have been not been reported in association with disease at this codon or nearby codons. Prevalence in the general population: Per varsome.com, this variant is present in 1 individual, but did not pass filtering tests. Thus, there is no variation at codon 1736 listed in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. The average coverage at that site in exome samples is 51.1x and in genome samples is 34.3x.

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