ClinVar Miner

Submissions for variant NM_001458.5(FLNC):c.4310T>C (p.Val1437Ala)

gnomAD frequency: 0.00001  dbSNP: rs754170282
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000649157 SCV000770982 uncertain significance Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant 2024-01-20 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 1437 of the FLNC protein (p.Val1437Ala). This variant is present in population databases (rs754170282, gnomAD 0.007%). 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: 539423). 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 RCV001771895 SCV002002487 uncertain significance not provided 2021-01-17 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID#539423; Landrum et al., 2016)
AiLife Diagnostics, AiLife Diagnostics RCV001771895 SCV002502277 uncertain significance not provided 2021-08-27 criteria provided, single submitter clinical testing
Ambry Genetics RCV003362878 SCV004054512 uncertain significance Cardiovascular phenotype 2023-08-03 criteria provided, single submitter clinical testing The p.V1437A variant (also known as c.4310T>C), located in coding exon 25 of the FLNC gene, results from a T to C substitution at nucleotide position 4310. The valine at codon 1437 is replaced by alanine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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