ClinVar Miner

Submissions for variant NM_001458.4(FLNC):c.3005G>A (p.Arg1002Gln) (rs202039743)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000658214 SCV000779985 uncertain significance not provided 2018-12-19 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the FLNC gene. The R1002Q variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R1002Q variant is observed in 7/126432 (0.01%) alleles from individuals of European background (Lek et al., 2016). The R1002Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, 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 a pathogenic variant or a rare benign variant.
Invitae RCV000540744 SCV000650969 uncertain significance Myofibrillar myopathy, filamin C-related; Myopathy, distal, 4; Cardiomyopathy, familial hypertrophic, 26; Dilated Cardiomyopathy, Dominant 2016-11-28 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 1002 of the FLNC protein (p.Arg1002Gln). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs202039743, ExAC 0.003%) but has not been reported in the literature in individuals with a FLNC-related disease. 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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