Submissions for variant NM_001458.5(FLNC):c.2635C>T (p.Arg879Cys)

gnomAD frequency: 0.00021  dbSNP: rs374983276

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000536582	SCV000650957	likely benign	Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant	2024-01-22	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV001508592	SCV001714854	uncertain significance	not provided	2019-10-20	criteria provided, single submitter	clinical testing
GeneDx	RCV001508592	SCV001765257	uncertain significance	not provided	2019-10-29	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID# 472016; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect
Ambry Genetics	RCV002438463	SCV002744754	uncertain significance	Cardiovascular phenotype	2023-03-10	criteria provided, single submitter	clinical testing	The p.R879C variant (also known as c.2635C>T), located in coding exon 17 of the FLNC gene, results from a C to T substitution at nucleotide position 2635. The arginine at codon 879 is replaced by cysteine, an amino acid with highly dissimilar properties. 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	RCV002506359	SCV002815302	uncertain significance	Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26	2021-10-20	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001508592	SCV003831419	uncertain significance	not provided	2023-04-30	criteria provided, single submitter	clinical testing
Institute of Immunology and Genetics Kaiserslautern	RCV003591750	SCV004363638	uncertain significance	Hypertrophic cardiomyopathy 26	2024-02-02	criteria provided, single submitter	clinical testing	ACMG Criteria : PM2_P,PP3; Variant was found in heterozygous state
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004525971	SCV005040398	likely benign	not specified	2024-03-05	criteria provided, single submitter	clinical testing	Variant summary: FLNC c.2635C>T (p.Arg879Cys) results in a non-conservative amino acid change in 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 0.00012 in 245752 control chromosomes. The observed variant frequency is approximately 15.63 fold of the estimated maximal expected allele frequency for a pathogenic variant in FLNC causing Dilated Cardiomyopathy phenotype (7.8e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.2635C>T in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 472016). Based on the evidence outlined above, the variant was classified as likely benign.