ClinVar Miner

Submissions for variant NM_001458.5(FLNC):c.3499C>T (p.Arg1167Cys)

gnomAD frequency: 0.00002  dbSNP: rs766439553
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000696166 SCV000824715 uncertain significance Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant 2024-01-22 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1167 of the FLNC protein (p.Arg1167Cys). This variant is present in population databases (rs766439553, gnomAD 0.006%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 31513939). ClinVar contains an entry for this variant (Variation ID: 574272). 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.
Athena Diagnostics RCV000711680 SCV000842067 uncertain significance not provided 2018-07-23 criteria provided, single submitter clinical testing
Center for Human Genetics, University of Leuven RCV000768503 SCV000886808 uncertain significance Hypertrophic cardiomyopathy 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000711680 SCV002032576 uncertain significance not provided 2021-11-30 criteria provided, single submitter clinical testing Reported in a patient with HCM, though additional clinical data were not provided (Robyns et al., 2020); Not observed at 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 as a variant of uncertain significance (ClinVar Variant ID# 574272; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 31513939, 26582918)
Ambry Genetics RCV002458257 SCV002614878 uncertain significance Cardiovascular phenotype 2023-12-13 criteria provided, single submitter clinical testing The p.R1167C variant (also known as c.3499C>T), located in coding exon 21 of the FLNC gene, results from a C to T substitution at nucleotide position 3499. The arginine at codon 1167 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in a hypertrophic cardiomyopathy (HCM) cohort and in a control population for a frontotemporal dementia (FTD) cohort (Janssens J et al. Acta Neuropathol Commun, 2015 Nov;3:68; Robyns T et al. Eur J Med Genet, 2020 Mar;63:103754). This amino acid position is 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.

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