Submissions for variant NM_001458.5(FLNC):c.3791-1G>C

gnomAD frequency: 0.00001  dbSNP: rs781135153

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000483809	SCV000568783	pathogenic	not provided	2022-09-08	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease (Shimrit et al., 2020); This variant is associated with the following publications: (PMID: 27896284, 25179549, 25633252, 27908349, 31775751, 32112656, 32532510)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000799570	SCV000939240	pathogenic	Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant	2024-11-28	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 21 of the FLNC gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in FLNC are known to be pathogenic (PMID: 27908349). This variant is present in population databases (rs781135153, gnomAD 0.02%). Disruption of this splice site has been observed in individuals with dilated cardiomyopathy (PMID: 25633252, 27908349). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 420146). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV001332010	SCV001524193	pathogenic	Hypertrophic cardiomyopathy 26	2022-02-07	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000483809	SCV002023737	pathogenic	not provided	2019-07-23	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004787779	SCV002557100	pathogenic	Primary dilated cardiomyopathy	2024-10-10	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene. Loss of function is the established mechanism of disease for variants in dilated cardiomyopathy (PMID: 32112656), familial hypertrophic cardiomyopathy 26 (MIM#617047), familial restrictive cardiomyopathy 5 (MIM#617047), familial arrhythmogenic right ventricular dysplasia (MIM#617047), and myofibrillar myopathy 5 (MIM#609524). In distal myopathy 4 (MIM#614065), NMD-predicted variants cause a loss of function, however missense variants have been shown to result in a toxic gain of function (PMID: 32112656). (I) 0107 - This gene is associated with autosomal dominant disease. Variants located throughout the gene that are predicted to result in nonsense-mediated decay (NMD) are enriched in dilated cardiomyopathy, whereas missense variants in the ROD2 domain are enriched in familial hypertrophic cardiomyopathy 26 and familial restrictive cardiomyopathy 5 (MIM#617047). Additionally, myofibrillar myopathy 5 (MIM#609524) is known to result from either missense variants in the ROD2 domain or truncating variants in the Ig-like domain 24, while missense variants in the actin-binding domain and NMD-predicted variants located in the Ig-like domain 15 and have been reported for distal myopathy 4 (MIM#614065) (PMID: 32112656). (I) 0115 - Variants in this gene are known to have variable expressivity in relation to arrhythmogenic right ventricular cardiomyopathy (PMID: 31627847). (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v4) <0.001 for a dominant condition (8 heterozygotes, 0 homozygote), with an Ashkenazi Jewish population bias (0.02%). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0703 - Other canonical splice site variants comparable to the one identified in this case have limited previous evidence of pathogenicity. c.3791-1G>A has been reported in two individuals with DCM (PMIDs: 27908349, 30067491) and c.3791-2A>T has been reported as a variant of uncertain significance by a clinical laboratory (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with DCM (ClinVar, PMIDs: 25633252, 25179549, 27908349, 32532510, VCGS Internal Database). (SP) 0902 - This variant has moderate evidence for segregation with disease (PMID: 32532510). (SP) 1007 - No published functional evidence has been identified for this variant. RP-PCR showed a reduction in FLNC transcript but didn't show any aberrant splicing (PMID: 32532510). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Ambry Genetics	RCV002356781	SCV002623320	pathogenic	Cardiovascular phenotype	2025-02-11	criteria provided, single submitter	clinical testing	The c.3791-1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide before coding exon 22 of the FLNC gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and may result in the creation or strengthening of a novel splice acceptor site. A resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNA decay; however, one study found this alteration resulted in reduced levels of the full length RNA transcript without evidence of any shorter transcript, suggestive of the occurrence of nonsense-mediated mRNA decay (Oz S et al. Int J Cardiol, 2020 Oct;317:133-138). This variant was identified in one or more individuals with features consistent with FLNC-related dilated cardiomyopathy, segregated with disease in at least one family, and has been proposed as an Ashkenazi Jewish founder mutation (Deo RC et al. Genome Biol., 2014 Dec;15:534; Golbus JR et al. Circ Cardiovasc Genet, 2014 Dec;7:751-759; Ortiz-Genga MF et al. J. Am. Coll. Cardiol., 2016 Dec;68:2440-2451; Oz S et al. Int J Cardiol, 2020 Oct;317:133-138; Ambry Internal Data). This nucleotide position is highly conserved in available vertebrate species. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation for FLNC-related dilated cardiomyopathy; however, its clinical significance for FLNC-related hypertrophic/restrictive cardiomyopathy and/or skeletal myopathy is uncertain.
New York Genome Center	RCV001332010	SCV004176050	pathogenic	Hypertrophic cardiomyopathy 26	2023-05-23	criteria provided, single submitter	clinical testing	The c.3791-1G>C variant in FLNC has previously been reported in multiple individuals with dilated cardiomyopathy [PMID: 25633252, 27908349, 25179549,32532510] and found to be segregated with disease in three families [PMID:32532510]. The variant has been deposited in ClinVar [ClinVar ID: 420146] as Likely Pathogenic/Pathogenic. The c.3791-1G>C variant is observed in 7 alleles (~0.0013% minor allele frequency with 0 homozygotes) in population databases (gnomADv2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases. The c.3791-1G>C variant in FLNC is located in the canonical splice acceptor site preceding exon 22 of this 48-exon gene and is presumed to affect mRNA splicing which might result in exon skipping or full/partial intron retention (Splice AI = 0.98). RT-PCR analysis using patient’s skin fibroblasts cells carrying c.3791-1G>C variant demonstrated a reductionin total FLNC transcript leading to complete absence of mRNA suggestive of NMD mechanism [PMID: 32532510]. Other canonical splice site (c.3791-1G>A) variant affecting the same nucleotide has been reported in individuals with dilated cardiomyopathy (PMID: 30067491, 31514951). Based on available evidence this c.3791-1G>C variant identified in FLNC is classified as Pathogenic.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000483809	SCV005197967	pathogenic	not provided	2024-03-20	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV001332010	SCV005368170	likely pathogenic	Hypertrophic cardiomyopathy 26	2024-07-09	criteria provided, single submitter	clinical testing	Criteria applied: PVS1_STR,PS4_MOD
PreventionGenetics, part of Exact Sciences	RCV004748783	SCV005349588	pathogenic	FLNC-related disorder	2024-07-03	no assertion criteria provided	clinical testing	The FLNC c.3791-1G>C variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been reported in several individuals with variable cardiac syndromes (Deo et al. 2014. PubMed ID: 25633252; Golbus et al. 2014. PubMed ID: 25179549; Oz et al. 2020. PubMed ID: 32532510). This variant was reported in two unrelated families with arrhythmogenic dilated cardiomyopathy and family history of sudden death (See family 27103 and family 48102 in Ortiz-Genga et al. 2016. PubMed ID: 27908349). This variant has also been reported to segregate with variable expression of arrhythmogenic cardiomyopathy in three unrelated Ashkenazi Jewish families as well (Oz et al. 2020. PubMed ID: 32532510). In this study, RNA analysis indicated a reduction in FLNC transcript and the authors suggest a haploinsufficiency genetic mechanism. In addition, a different nucleotide change at the same position (c.3791-1G>A) has also been observed in several individuals with arrhythmogenic dilated cardiomyopathy (Ortiz-Genga et al. 2016. PubMed ID: 27908349; Begay et al. 2018. PubMed ID: 30067491). This variant is reported in 0.020% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. Variants that disrupt the consensus splice acceptor site in FLNC are expected to be pathogenic. This variant is interpreted as pathogenic.