Submissions for variant NM_001458.5(FLNC):c.469C>G (p.Arg157Gly)

dbSNP: rs759739899

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000424843	SCV000535150	uncertain significance	not provided	2016-12-15	criteria provided, single submitter	clinical testing	The R157G variant in the FLNC gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R157G variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R157G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where amino acids with similar properties to Arginine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret R157G as a variant of uncertain significance.
Invitae	RCV001299637	SCV001488739	uncertain significance	Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant	2024-01-26	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 157 of the FLNC protein (p.Arg157Gly). This variant is present in population databases (rs759739899, gnomAD 0.003%). 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: 391973). 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.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224280	SCV003919975	uncertain significance	Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26	2021-03-30	criteria provided, single submitter	clinical testing	FLNC NM_001458.4 exon 2 p.Arg157Gly (c.469C>G): This variant has not been reported in the literature and is present in 0.003% (1/30610) of South Asian alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/7-128475496-C-G). This variant is present in ClinVar (Variation ID:391973). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Ambry Genetics	RCV004022501	SCV005017849	uncertain significance	Cardiovascular phenotype	2023-12-06	criteria provided, single submitter	clinical testing	The p.R157G variant (also known as c.469C>G), located in coding exon 2 of the FLNC gene, results from a C to G substitution at nucleotide position 469. The arginine at codon 157 is replaced by glycine, an amino acid with dissimilar 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.