ClinVar Miner

Submissions for variant NM_001458.4(FLNC):c.6799G>A (p.Val2267Ile) (rs758080422)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000518871 SCV000619027 uncertain significance not provided 2018-09-17 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the FLNC gene. The V2267I variant has previously been reported in an individual with nemaline myopathy, however, additional detailed clinical information and segregation analysis was not provided (Savarese et al., 2014). This variant is observed in 7/102,928 alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). V2267I is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Furthermore, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Invitae RCV001042328 SCV001206004 uncertain significance Myofibrillar myopathy, filamin C-related; Myopathy, distal, 4; Cardiomyopathy, familial hypertrophic, 26; Dilated Cardiomyopathy, Dominant 2020-01-13 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 2267 of the FLNC protein (p.Val2267Ile). The valine residue is moderately conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs758080422, ExAC 0.01%). This variant has not been reported in the literature in individuals with FLNC-related conditions. ClinVar contains an entry for this variant (Variation ID: 450440). 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.

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