Submissions for variant NM_001458.5(FLNC):c.1081C>T (p.Arg361Cys)

gnomAD frequency: 0.00016  dbSNP: rs200206944

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000540279	SCV000650883	benign	Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant	2024-01-20	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000764683	SCV000895815	uncertain significance	Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26	2018-10-31	criteria provided, single submitter	clinical testing
GeneDx	RCV001528916	SCV001756303	likely benign	not provided	2019-11-08	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID 441151; Landrum et al., 2016); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 28492532, 25741868)
Ambry Genetics	RCV002431471	SCV002729238	likely benign	Cardiovascular phenotype	2023-11-16	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Revvity Omics, Revvity	RCV001528916	SCV003833096	uncertain significance	not provided	2023-05-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003403197	SCV004122805	likely benign	not specified	2023-10-12	criteria provided, single submitter	clinical testing	Variant summary: FLNC c.1081C>T (p.Arg361Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 249556 control chromosomes. The observed variant frequency is approximately 21 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.1081C>T in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as benign/likely benign (n=2) and VUS (n=3). Based on the evidence outlined above, the variant was classified as likely benign.
GenomeConnect, ClinGen	RCV000509189	SCV000607328	not provided	Myofibrillar myopathy 5		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.