Submissions for variant NM_001458.5(FLNC):c.4276C>T (p.Arg1426Trp)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002330067	SCV002631584	uncertain significance	Cardiovascular phenotype	2020-10-02	criteria provided, single submitter	clinical testing	The p.R1426W variant (also known as c.4276C>T), located in coding exon 24 of the FLNC gene, results from a C to T substitution at nucleotide position 4276. The arginine at codon 1426 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV003102554	SCV002978124	uncertain significance	Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant	2023-04-20	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: 1739292). This variant has not been reported in the literature in individuals affected with FLNC-related conditions. This variant is present in population databases (rs763218103, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1426 of the FLNC protein (p.Arg1426Trp).
PreventionGenetics, part of Exact Sciences	RCV003403792	SCV004105495	uncertain significance	FLNC-related disorder	2023-08-24	criteria provided, single submitter	clinical testing	The FLNC c.4276C>T variant is predicted to result in the amino acid substitution p.Arg1426Trp. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-128486947-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Revvity Omics, Revvity	RCV003491090	SCV004234808	uncertain significance	not provided	2023-03-21	criteria provided, single submitter	clinical testing