Submissions for variant NM_001458.5(FLNC):c.6976C>T (p.Arg2326Ter)

dbSNP: rs748416758

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000554323	SCV000659721	pathogenic	Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant	2023-05-05	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: 478129). This premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy (PMID: 27908349). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs748416758, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Arg2326*) 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	RCV001571673	SCV001796185	pathogenic	not provided	2022-08-15	criteria provided, single submitter	clinical testing	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; Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 478129; ClinVar); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27908349, 28416588, 28436997, 31514951)
Ambry Genetics	RCV002367971	SCV002664413	pathogenic	Cardiovascular phenotype	2021-12-09	criteria provided, single submitter	clinical testing	The p.R2326* pathogenic mutation (also known as c.6976C>T), located in coding exon 41 of the FLNC gene, results from a C to T substitution at nucleotide position 6976. This changes the amino acid from an arginine to a stop codon within coding exon 41. This alteration has been reported in multiple individuals with dilated cardiomyopathy, including segregating with disease in one family (Ortiz-Genga MF et al. J Am Coll Cardiol, 2016 Dec;68:2440-2451; Dal Ferro M et al. Heart, 2017 11;103:1704-1710; Janin A et al. Clin Genet, 2017 Dec;92:616-623). 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003150276	SCV003838451	pathogenic	Cardiomyopathy	2021-09-20	criteria provided, single submitter	clinical testing