Submissions for variant NM_001458.5(FLNC):c.6031G>A (p.Gly2011Arg)

dbSNP: rs1554400962

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000549865	SCV000651104	pathogenic	Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant	2023-12-13	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 2011 of the FLNC protein (p.Gly2011Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of FLNC-related conditions (PMID: 32659924; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 472122). 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. This variant disrupts the p.Gly2011 amino acid residue in FLNC. Other variant(s) that disrupt this residue have been observed in individuals with FLNC-related conditions (PMID: 30418145), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001770467	SCV001993204	likely pathogenic	not provided	2022-07-28	criteria provided, single submitter	clinical testing	Identified in patients with restrictive cardiomyopathy referred for genetic testing at GeneDx and in published literature (Herenandez et al., 2020; Kolokotronis et al., 2020; Lopes et al., 2021; Perepelina et al., 2021); at least one of these individuals harbored an additional cardiogenetic variant; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34971931, 35456187, 34263907, Hernandez2020, 32659924)
Ambry Genetics	RCV004024197	SCV005017746	uncertain significance	Cardiovascular phenotype	2024-01-05	criteria provided, single submitter	clinical testing	The p.G2011R variant (also known as c.6031G>A), located in coding exon 37 of the FLNC gene, results from a G to A substitution at nucleotide position 6031. The glycine at codon 2011 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been reported in individuals with restrictive cardiomyopathy (RCM) (Kolokotronis K et al. J Clin Med, 2020 Jul;9:[ePub ahead of print]; Lopes LR et al. Eur Heart J, 2021 Aug;42:3063-3073). 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.
Institute of Human Genetics, University of Wuerzburg	RCV000850350	SCV000992526	likely pathogenic	Restrictive cardiomyopathy		no assertion criteria provided	clinical testing