Submissions for variant NM_001458.5(FLNC):c.5194G>A (p.Val1732Met)

dbSNP: rs374848954

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000797781	SCV000937360	likely benign	Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant	2023-12-22	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002272359	SCV002557671	uncertain significance	Primary dilated cardiomyopathy	2022-06-24	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. 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 (MONDO#0005021), FLNC-related, as well as hypertrophic cardiomyopathy, restrictive cardiomyopathy (MIM#617047) and myofibrillar myopathy (MIM#609524). Recently it has also been associated with arrhythmogenic right ventricular cardiomyopathy (ARVC; PMID: 31627847). 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) 0200 - Variant is predicted to result in a missense amino acid change from valine to methionine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (v2: 4 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2 and v3: 2 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated filamin 15 domain within the ROD1 domain (UniProt and PMID: 32112656). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. It has been reported as VUS once in ClinVar. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (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	RCV002334495	SCV002643770	uncertain significance	Cardiovascular phenotype	2023-10-26	criteria provided, single submitter	clinical testing	The p.V1732M variant (also known as c.5194G>A), located in coding exon 30 of the FLNC gene, results from a G to A substitution at nucleotide position 5194. The valine at codon 1732 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
New York Genome Center	RCV003336191	SCV004046557	uncertain significance	Hypertrophic cardiomyopathy 26	2023-03-10	criteria provided, single submitter	clinical testing	The c.5194G>A, p.(Val1732Met) variant identified in the FLNC gene is a missense variant predicted to substitute a Valine for Methionine at amino acid 1732/2762 (exon 30/48). This variant is found with low frequency in population databases (gnomADv2.1.1, gnomADv3.1.2, BRAVO-TOPMed,All of US; allele frequency: 3.07e-5, 0 homozygotes) suggesting it is not a common benign variant in the populations represented in those databases. The c.5194G>A,p.(Val1732Met) variant has been reported in ClinVar as both a Variant of Uncertain Significance and Likely Benign (VarID:643960), and to our current knowledge has not been reported in affected individuals in the literature. Given the lack of compelling evidence for its pathogenicity, the c.5194G>A, p.(Val1732Met) variant identified in the FLNC gene is reported as a Variant of Uncertain Significance.