Submissions for variant NM_001458.5(FLNC):c.3937C>T (p.Arg1313Ter)

dbSNP: rs766330686

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000702917	SCV000831793	pathogenic	Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant	2023-07-19	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 579589). This variant has not been reported in the literature in individuals affected with FLNC-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg1313*) in the FLNC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FLNC are known to be pathogenic (PMID: 27908349).
GeneDx	RCV001546472	SCV001765996	likely pathogenic	not provided	2023-03-08	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease
Ambry Genetics	RCV002352198	SCV002621753	pathogenic	Cardiovascular phenotype	2022-04-08	criteria provided, single submitter	clinical testing	The p.R1313* pathogenic mutation (also known as c.3937C>T), located in coding exon 22 of the FLNC gene, results from a C to T substitution at nucleotide position 3937. This changes the amino acid from an arginine to a stop codon within coding exon 22. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Molecular Genetics, Royal Melbourne Hospital	RCV003994088	SCV004812867	pathogenic	Primary dilated cardiomyopathy	2023-09-04	criteria provided, single submitter	clinical testing	This sequence change in FLNC is a nonsense variant predicted to cause a premature stop codon, p.(Arg1313*), in biologically relevant exon 22/48 leading to nonsense-mediated decay in a gene in which loss of function is an established disease mechanism. This variant is absent from the population database gnomAD v2.1 and v3.1. This variant has been reported in at least two probands with dilated cardiomyopathy (PMID: 34535832; Royal Melbourne Hospital). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PM2_Supporting, PS4_Supporting.