Submissions for variant NM_001458.5(FLNC):c.5888C>T (p.Thr1963Met)

gnomAD frequency: 0.00009  dbSNP: rs772580545

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000687414	SCV000814978	likely benign	Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant	2024-01-17	criteria provided, single submitter	clinical testing
GeneDx	RCV001528483	SCV001796580	uncertain significance	not provided	2020-05-11	criteria provided, single submitter	clinical testing	Reported in an individual with HCM (Cui et al., 2018); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 567356; Landrum et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30411535)
Ambry Genetics	RCV002352124	SCV002652524	uncertain significance	Cardiovascular phenotype	2023-04-26	criteria provided, single submitter	clinical testing	The p.T1963M variant (also known as c.5888C>T), located in coding exon 36 of the FLNC gene, results from a C to T substitution at nucleotide position 5888. The threonine at codon 1963 is replaced by methionine, an amino acid with similar properties. This variant has been detected in an individual from a hypertrophic cardiomyopathy cohort; however, details were limited (Cui H et al. Mol Genet Genomic Med, 2018 11;6:1104-1113). This amino acid position is 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470951	SCV002767352	uncertain significance	Hypertrophic cardiomyopathy 26	2021-05-06	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, 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). 0200 - Variant is predicted to result in a missense amino acid change from threonine to methionine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (13 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated immunoglobulin (Ig)-like 18 repeat of the ROD2 domain (PMID: 32112656). (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. An alternate change to lysine at the same residue has previously been reported as a VUS (ClinVar). (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. The variant has previously been reported in association with HCM and has been classified as a VUS in at least four individuals (ClinVar, LOVD, PMID: 30411535, PMID: 32112656). (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
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001528483	SCV001740304	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001528483	SCV001932822	uncertain significance	not provided		no assertion criteria provided	clinical testing