ClinVar Miner

Submissions for variant NM_001458.5(FLNC):c.490C>T (p.Arg164Trp)

gnomAD frequency: 0.00001  dbSNP: rs1460797312
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000702537 SCV000831395 uncertain significance Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant 2023-05-26 criteria provided, single submitter clinical testing 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. 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. ClinVar contains an entry for this variant (Variation ID: 579294). This missense change has been observed in individual(s) with left ventricular non-compaction (PMID: 31918855). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 164 of the FLNC protein (p.Arg164Trp).
GeneDx RCV001771994 SCV002002037 uncertain significance not provided 2020-02-03 criteria provided, single submitter clinical testing 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; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 31918855)
Ambry Genetics RCV002334359 SCV002644455 uncertain significance Cardiovascular phenotype 2022-03-11 criteria provided, single submitter clinical testing The p.R164W variant (also known as c.490C>T), located in coding exon 2 of the FLNC gene, results from a C to T substitution at nucleotide position 490. The arginine at codon 164 is replaced by tryptophan, an amino acid with dissimilar properties. This variant was reported in one individual with left ventricular non-compaction (LVNC), who also had additional co-occurring cardiac variants detected (Liu S et al. Int J Cardiol, 2020 03;302:117-123). This amino acid position is highly conserved in available vertebrate species. 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV002470958 SCV002766734 uncertain significance Primary dilated cardiomyopathy 2021-05-06 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with FLNC-related disease. Loss of function variants have been reported to cause myofibrillar myopathy, 5 (MIM#609524), distal myopathy, 4 (MIM#614065), familial hypertrophic cardiomyopathy, 26 (MIM#617047) and dilated cardiomyopathy (PMID: 32112656). Gain of function variants have also been reported to cause distal myopathy, 4 (MIM#614065) (PMID: 28008423, PMID: 23109048). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2, v3) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated calponin homology domain (Uniprot). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been previously reported as a VUS (ClinVar). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.