Submissions for variant NM_001458.5(FLNC):c.5284C>T (p.Arg1762Cys)

gnomAD frequency: 0.00026  dbSNP: rs201926772

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001034665	SCV000651070	likely benign	Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant	2024-01-19	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000555159	SCV001155274	likely benign	not provided	2018-04-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000555159	SCV001888893	benign	not provided	2020-10-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002350345	SCV002645234	likely benign	Cardiovascular phenotype	2022-01-26	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	RCV000555159	SCV003833163	likely benign	not provided	2023-03-15	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV003338663	SCV004048292	uncertain significance	Hypertrophic cardiomyopathy 26		criteria provided, single submitter	clinical testing	The missense variant c.5284C>T (p.Arg1762Cys) in FLNC gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The variant has been submitted to ClinVar with conflicting interpretations of Uncertain Significance/Likely Benign. The p.Arg1762Cys variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.02512% is reported in gnomAD. The amino acid Arg at position 1762 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. In silico tools predict the variant to be tolerated. The residue is conserved across species. The amino acid change p.Arg1762Cys in FLNC is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The cysteine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. For these reasons, this variant has been classified as Uncertain Significance .