ClinVar Miner

Submissions for variant NM_001458.5(FLNC):c.4660A>C (p.Ile1554Leu)

gnomAD frequency: 0.00004  dbSNP: rs754224673
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000649104 SCV000770929 uncertain significance Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant 2022-09-24 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1554 of the FLNC protein (p.Ile1554Leu). This variant is present in population databases (rs754224673, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with FLNC-related conditions. ClinVar contains an entry for this variant (Variation ID: 539376). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FLNC protein function. 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.
GeneDx RCV001766402 SCV001998535 uncertain significance not provided 2019-11-21 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 539376; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function
Ambry Genetics RCV002331235 SCV002634311 uncertain significance Cardiovascular phenotype 2023-10-31 criteria provided, single submitter clinical testing The p.I1554L variant (also known as c.4660A>C), located in coding exon 27 of the FLNC gene, results from an A to C substitution at nucleotide position 4660. The isoleucine at codon 1554 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity RCV001766402 SCV003833040 uncertain significance not provided 2022-03-14 criteria provided, single submitter clinical testing

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