Submissions for variant NM_001458.5(FLNC):c.7382G>A (p.Ser2461Asn)

gnomAD frequency: 0.00002  dbSNP: rs550547714

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000267784	SCV000334368	uncertain significance	not provided	2015-08-25	criteria provided, single submitter	clinical testing
Invitae	RCV000699663	SCV000828385	uncertain significance	Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 2461 of the FLNC protein (p.Ser2461Asn). This variant is present in population databases (rs550547714, gnomAD 0.005%). This missense change has been observed in individual(s) with frontotemporal dementia and/or muscle weakness (PMID: 26555887, 31127727). ClinVar contains an entry for this variant (Variation ID: 282755). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The asparagine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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.
GeneDx	RCV000267784	SCV001816213	uncertain significance	not provided	2019-09-11	criteria provided, single submitter	clinical testing	Has not been previously reported in association with FLNC-related disease to our knowledge; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 282755; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31127727, 26555887)
Ambry Genetics	RCV002379116	SCV002672396	uncertain significance	Cardiovascular phenotype	2019-12-19	criteria provided, single submitter	clinical testing	The p.S2461N variant (also known as c.7382G>A), located in coding exon 44 of the FLNC gene, results from a G to A substitution at nucleotide position 7382. The serine at codon 2461 is replaced by asparagine, an amino acid with highly similar properties. This variant was detected in one individual from a frontotemporal dementia cohort with no known myopathy findings (Janssens J et al. Acta Neuropathol Commun, 2015 Nov;3:68). This amino acid position is well conserved in available vertebrate species; however, asparagine is the reference amino acid in other 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.
Revvity Omics, Revvity	RCV000267784	SCV003833070	uncertain significance	not provided	2020-12-31	criteria provided, single submitter	clinical testing
Clinical Genetics, Academic Medical Center	RCV000267784	SCV001919554	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000267784	SCV001929813	uncertain significance	not provided		no assertion criteria provided	clinical testing