Submissions for variant NM_001458.5(FLNC):c.6209-3C>G

gnomAD frequency: 0.00002  dbSNP: rs896971028

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000649132	SCV000770957	uncertain significance	Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant	2022-10-30	criteria provided, single submitter	clinical testing	This sequence change falls in intron 37 of the FLNC gene. It does not directly change the encoded amino acid sequence of the FLNC protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (no rsID available, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with FLNC-related conditions. ClinVar contains an entry for this variant (Variation ID: 539402). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV001766403	SCV001991962	uncertain significance	not provided	2019-04-09	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Observed in 0.0022% (6/276758) of global alleles in large population cohorts (Lek et al., 2016); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 539402; Landrum et al., 2016); In silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect; Several other splicing variants in FLNC are reported in HGMD in association with cardiomyopathy, although the majority are located upstream of this variant (Stenson et al., 2014)
Revvity Omics, Revvity	RCV001766403	SCV003831438	uncertain significance	not provided	2019-06-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004025772	SCV005017813	uncertain significance	Cardiovascular phenotype	2023-11-07	criteria provided, single submitter	clinical testing	The c.6209-3C>G intronic variant results from a C to G substitution 3 nucleotides upstream from coding exon 38 in the FLNC gene. This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.