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

gnomAD frequency: 0.00001  dbSNP: rs781135153

Total submissions: 7

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)
Invitae	RCV000799570	SCV000939240	pathogenic	Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant	2023-11-14	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	RCV001332010	SCV002557100	likely pathogenic	Hypertrophic cardiomyopathy 26	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely 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, hypertrophic cardiomyopathy, restrictive cardiomyopathy (MIM#617047) and myofibrillar myopathy (MIM#609524). In distal myopathy (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 hypertrophic cardiomyopathy and restrictive cardiomyopathy (MIM#617047). Additionally, myofibrillar myopathy (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 (MIM#614065) (PMID: 32112656). (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 (v2) <0.001 for a dominant condition (3 heterozygotes, 0 homozygote), with an Ashkenazi Jewish population bias (0.02%). (SP) 0703 - Other canonical splice site variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. Another canonical splice site variant, c.3791-1G>A, has been reported in two DCM individuals (PMID: 27908349, 30067491), and c.3791-1del has been reported once in a HCM individual (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This vairant has been reported in multiple individuals with DCM (ClinVar, PMID: 25633252, 25179549, 27908349, 32532510). (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	2021-12-13	criteria provided, single submitter	clinical testing	The c.3791-1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide upstream from coding exon 22 of the FLNC gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay (NMD), however one splicing prediction for this alteration results in the in-frame deletion of exon 22, for which the exact functional impact is unknown. One study found this alteration resulted in reduced levels of the full length RNA transcript without evidence of any shorter transcript, which is suggestive of the occurrence of NMD (Oz S et al. Int J Cardiol, 2020 Oct;317:133-138). This mutation has been detected in individuals reported to have dilated cardiomyopathy (DCM) and arrhythmia (Deo RC et al. Genome Biol., 2014 Dec;15:534; Golbus JR et al. Circ Cardiovasc Genet, 2014 Dec;7:751-759; Ambry Internal Data). Additionally, moderate segregation with ventricular dysfunction and DCM was observed among three families of Ashkenazi Jewish ancestry (Oz S et al. Int J Cardiol, 2020 Oct;317:133-138), and in siblings from one family with ventricular arrhythmia who did not have significantly reduced left ventricular function (Ortiz-Genga MF et al. J. Am. Coll. Cardiol., 2016 Dec;68:2440-2451). This variant has been detected in three alleles in the gnomAD database, where the highest observed frequency was 0.02% (2/10044) of Ashkenazi Jewish alleles, and it has been suggested to be a founder mutation in that subpopulation (Oz S et al. Int J Cardiol, 2020 Oct;317:133-138). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
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.