Submissions for variant NM_001458.5(FLNC):c.3133C>A (p.His1045Asn)

gnomAD frequency: 0.00004  dbSNP: rs201863231

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000497327	SCV000590513	uncertain significance	not provided	2017-06-23	criteria provided, single submitter	clinical testing	The c.3133 C>A variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.3133 C>A variant is observed in 6/63416 (0.01%) alleles from individuals of European background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Multiple in-silico splice prediction models predict that c.3133 C>A creates a cryptic splice donor site which may supplant the natural donor site and lead to abnormal gene splicing. However, in the absence of RNA/functional studies the actual effect of c.3133 C>A on splicing in this individual is unknown. If c.3133 C>A does not alter splicing, it will result in the H1045N missense change. The H1045N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals; however, missense variants in nearby residues have not been reported in the Human Gene Mutation Database in association with FLNC-related disorders (Stenson et al., 2014). In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Invitae	RCV000701577	SCV000830384	likely benign	Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant	2024-01-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002323864	SCV002607457	uncertain significance	Cardiovascular phenotype	2022-12-19	criteria provided, single submitter	clinical testing	The p.H1045N variant (also known as c.3133C>A), located in coding exon 20 of the FLNC gene, results from a C to A substitution at nucleotide position 3133. The histidine at codon 1045 is replaced by asparagine, an amino acid with similar properties. This variant has been detected in a cohort in association with personal or family history of dilated cardiomyopathy (DCM) or suspicion of DCM; however, additional detail was limited (Smith E et al. J Am Heart Assoc, 2022 May;11:e024501). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002506207	SCV002816235	uncertain significance	Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26	2021-09-12	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000497327	SCV003833603	uncertain significance	not provided	2021-11-25	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003486853	SCV004240638	uncertain significance	Cardiomyopathy	2023-05-16	criteria provided, single submitter	clinical testing