Submissions for variant NM_001458.5(FLNC):c.7090C>T (p.Arg2364Cys)

gnomAD frequency: 0.00006  dbSNP: rs374973240

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000822078	SCV000962863	likely benign	Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV001357140	SCV001793210	uncertain significance	not provided	2021-03-04	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 664067; Landrum et al., 2016); 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: 25617006)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002307631	SCV002600684	uncertain significance	not specified	2022-10-23	criteria provided, single submitter	clinical testing	Variant summary: FLNC c.7090C>T (p.Arg2364Cys) results in a non-conservative amino acid change located in the Filamin/ABP280 repeat (IPR001298) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-05 in 249450 control chromosomes (gnomAD). The observed variant frequency is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant in FLNC causing Cardiomyopathy phenotype (1.1e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.7090C>T in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters have assessed the variant since 2014: both classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Ambry Genetics	RCV002363167	SCV002663081	uncertain significance	Cardiovascular phenotype	2022-04-29	criteria provided, single submitter	clinical testing	The p.R2364C variant (also known as c.7090C>T), located in coding exon 42 of the FLNC gene, results from a C to T substitution at nucleotide position 7090. The arginine at codon 2364 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration (described as R2331C) has been reported in a cohort of subjects with sporadic inclusion body myositis (Weihl CC et al. Neuromuscul. Disord., 2015 Apr;25:289-96). This amino acid position is highly 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.
Fulgent Genetics, Fulgent Genetics	RCV002495178	SCV002797687	uncertain significance	Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26	2021-08-18	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001357140	SCV003833141	uncertain significance	not provided	2021-05-18	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003396451	SCV004105273	uncertain significance	FLNC-related disorder	2022-11-10	criteria provided, single submitter	clinical testing	The FLNC c.7090C>T variant is predicted to result in the amino acid substitution p.Arg2364Cys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-128494921-C-T). A different nucleotide substitution affecting the same amino acid (p.Arg2364His) has been reported in an individual with myofibrillar myopathy (described as R2331H, Weihl et al. 2015. PubMed ID: 25617006). Although we suspect that the c.7090C>T (p.Arg2364Cys) variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
CeGaT Center for Human Genetics Tuebingen	RCV001357140	SCV004698370	uncertain significance	not provided	2023-12-01	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357140	SCV001552508	uncertain significance	not provided		no assertion criteria provided	clinical testing	The FLNC p.Arg2331Cys variant was identified in dbSNP (ID: rs374973240) and in ClinVar (classified as uncertain significance by Invitae) but was not identified in the literature or in LOVD 3.0. The variant was identified in control databases in 19 of 280826 chromosomes at a frequency of 0.000068 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: African in 3 of 24190 chromosomes (freq: 0.000124), European (non-Finnish) in 15 of 128596 chromosomes (freq: 0.000117) and East Asian in 1 of 19536 chromosomes (freq: 0.000051), but was not observed in the Latino, Ashkenazi Jewish, European (Finnish), South Asian or Other populations. The p.Arg2331 residue is conserved in across mammals and other organisms and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest a high likelihood of impact to the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.