ClinVar Miner

Submissions for variant NM_001458.4(FLNC):c.643G>A (p.Val215Met) (rs754309921)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Broad Institute Rare Disease Group,Broad Institute RCV000663409 SCV000786697 uncertain significance Myopathy, distal, 4 criteria provided, single submitter research The heterozygous p.Val215Met variant was identified by our study in one individual with distal myopathy. This variant has not been reported in the literature, however it has been reported in ClinVar by by one clinical laboartory (ID: 424399). This variant has been identified in present in European (7/115,048), African (3/21,944), and East Asian (1/18,074) chromosomes at 0.01% by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs754309921). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Val215Met variant is uncertain.
Fulgent Genetics,Fulgent Genetics RCV000765930 SCV000897350 uncertain significance Myofibrillar myopathy, filamin C-related; Myopathy, distal, 4; Cardiomyopathy, familial hypertrophic, 26 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000481861 SCV000574204 uncertain significance not provided 2018-07-05 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the FLNC gene. The V215M variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed at a global allele frequency of 12/255438 (0.005%) in large population cohorts (Lek et al., 2016). The V215M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function.
Invitae RCV000703450 SCV000832349 uncertain significance Myofibrillar myopathy, filamin C-related; Myopathy, distal, 4; Cardiomyopathy, familial hypertrophic, 26; Dilated Cardiomyopathy, Dominant 2018-09-17 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 215 of the FLNC protein (p.Val215Met). The valine residue is moderately conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs754309921, 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: 424399). 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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