ClinVar Miner

Submissions for variant NM_001458.4(FLNC):c.7289C>T (p.Ala2430Val) (rs200516164)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000178551 SCV000230652 uncertain significance not provided 2015-02-17 criteria provided, single submitter clinical testing
Invitae RCV000649080 SCV000770905 uncertain significance Myofibrillar myopathy, filamin C-related; Myopathy, distal, 4; Cardiomyopathy, familial hypertrophic, 26; Dilated Cardiomyopathy, Dominant 2020-09-24 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 2430 of the FLNC protein (p.Ala2430Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs200516164, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in the literature in individuals with hypertrophic cardiomyopathy (PMID: 25351925, 28356264). ClinVar contains an entry for this variant (Variation ID: 197502). 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.
Fulgent Genetics,Fulgent Genetics RCV000764688 SCV000895820 uncertain significance Myofibrillar myopathy, filamin C-related; Myopathy, distal, 4; Cardiomyopathy, familial hypertrophic, 26 2018-10-31 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000178551 SCV001247568 uncertain significance not provided 2020-01-01 criteria provided, single submitter clinical testing
GeneDx RCV000178551 SCV001790938 likely benign not provided 2020-12-23 criteria provided, single submitter clinical testing Reported in two probands with HCM; one of these probands also demonstrated elevated CK levels, and two out of three relatives who were heterozygous for A2430V demonstrated elevated CK levels and left ventricular wall measurements of 12 mm and 14 mm, respectively (Valdes-Mas et al., 2014; Gomez et al., 2017); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies suggest an effect on protein structure (Valdes-Mas et al., 2014); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 197502; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 26555887, 28356264, 25351925)
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000178551 SCV001926478 uncertain significance not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000178551 SCV001955144 uncertain significance not provided no assertion criteria provided clinical testing

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