Submissions for variant NM_001458.5(FLNC):c.4021C>T (p.Arg1341Ter)

dbSNP: rs1562998062

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000760746	SCV000890640	likely pathogenic	not provided	2018-09-17	criteria provided, single submitter	clinical testing	The R1341X variant in the FLNC gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R1341X variant is not observed in large population cohorts (Lek et al., 2016). We interpret R1341X as a likely pathogenic variant.
Blueprint Genetics	RCV000760746	SCV000927949	likely pathogenic	not provided	2018-09-21	criteria provided, single submitter	clinical testing
Invitae	RCV001067745	SCV001232819	pathogenic	Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant	2023-03-26	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 620373). This variant has not been reported in the literature in individuals affected with FLNC-related conditions. This sequence change creates a premature translational stop signal (p.Arg1341*) 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).
3billion	RCV001809795	SCV002058234	pathogenic	Hypertrophic cardiomyopathy 26	2022-01-03	criteria provided, single submitter	clinical testing	Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000620373). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Center for Human Genetics, University of Leuven	RCV003166019	SCV002581947	pathogenic	Primary familial dilated cardiomyopathy	2021-12-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002370018	SCV002625542	pathogenic	Cardiovascular phenotype	2023-12-05	criteria provided, single submitter	clinical testing	The p.R1341* pathogenic mutation (also known as c.4021C>T), located in coding exon 23 of the FLNC gene, results from a C to T substitution at nucleotide position 4021. This changes the amino acid from an arginine to a stop codon within coding exon 23. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is expected to be causative of dilated cardiomyopathy; however, its clinical significance for hypertrophic/restrictive cardiomyopathy and/or skeletal myopathy is unclear.
New York Genome Center	RCV001809795	SCV003925228	likely pathogenic	Hypertrophic cardiomyopathy 26	2022-09-26	criteria provided, single submitter	clinical testing	The c.4021C>T p.(Arg1341Ter) variant in the FLNC gene has previously been reported in an infant with dilated cardiomyopathy [PMID:31527676] and it has been deposited in ClinVar [ClinVar ID: 620373] as Likely Pathogenic/Pathogenic. The c.4021C>T variant is absent from population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases. The c.4021C>T variant in FLNC is located in exon 23 of this 48-exon gene, predicted to incorporate a premature termination codon (p.(Arg1341Ter)), and is expected to result in loss-of-function via nonsense mediated decay. Multiple loss-of-function variants that are downstream to the c.4021C>T variant have been reported in the literature [PMID:32112656] and ClinVar [ClinVar ID: 620418, 620286, others] in individuals with FLNC-related conditions. Based on available evidence this c.4021C>Tp.(Arg1341Ter) variant identified in FLNC is classified as Likely Pathogenic.
Illumina Laboratory Services, Illumina	RCV004547953	SCV004801409	pathogenic	FLNC-related disorder	2022-01-13	criteria provided, single submitter	clinical testing	The FLNC c.4021C>T p.(Arg1341Ter) nonsense variant results in the substitution of arginine at amino acid position 1341 with a stop codon. This variant disrupts exon 23 of 48 on the canonical transcript and loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay is expected. This variant has been reported in a heterozygous state in one individual with dilated cardiomyopathy (Burstein et al. 2020). Additionally, several disease-causing variants located downstream of the p.Arg1341Ter variant are reported in the peer-reviewed literature and ClinVar database (Ortiz-Genga et al. 2016; Landrum et al. 2018). This variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Based on the available evidence, the c.4021C>T p.(Arg1341Ter) variant is classified as pathogenic for FLNC-related disorders.
deCODE genetics, Amgen	RCV001809795	SCV004022148	likely pathogenic	Hypertrophic cardiomyopathy 26	2023-07-21	no assertion criteria provided	research	The variant NM_001458.5:c.4021C>T (chr7:128846357) in FLNC was detected in 1 heterozygote out of 58K WGS Icelanders (MAF= 0,001%). This variant has been reported in ClinVar previously as pathogenic. Based on ACMG criteria (PVS1, PM2) this variant classifies as likely pathogenic.