Submissions for variant NM_001458.5(FLNC):c.7226G>A (p.Arg2409His)

gnomAD frequency: 0.00001  dbSNP: rs767279710

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000649059	SCV000770884	likely benign	Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant	2023-06-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002369734	SCV002671398	uncertain significance	Cardiovascular phenotype	2023-03-13	criteria provided, single submitter	clinical testing	The p.R2409H variant (also known as c.7226G>A), located in coding exon 43 of the FLNC gene, results from a G to A substitution at nucleotide position 7226. The arginine at codon 2409 is replaced by histidine, 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470940	SCV002767353	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 (LoF) and gain of function (GoF) are known mechanisms of disease in this gene. Null variants enriched in dilated cardiomyopathy and distal myopathy (MIM#614065) while missense variants, mainly in the ROD2 domain, are enriched in hypertrophic cardiomyopathy, familial (MIM#617047), restrictive cardiomyopathy, familial (MIM#617047) and myofibrillar myopathy (MIM#609524) (PMID: 32112656). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (v2: 5 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2: 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 repeat (Uniprot, NCBI) (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. p.(Arg2409Cys) has been classified as a VUS by a diagnostic laboratory in ClinVar. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. It has been classified as a VUS by a diagnostic laboratory 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
Revvity Omics, Revvity	RCV003144433	SCV003833036	uncertain significance	not provided	2021-01-12	criteria provided, single submitter	clinical testing
Molecular Genetics, Royal Melbourne Hospital	RCV002470940	SCV004812477	uncertain significance	Hypertrophic cardiomyopathy 26	2023-04-11	criteria provided, single submitter	clinical testing	This sequence change in FLNC is predicted to replace arginine with histidine at codon 2409, p.(Arg2409His). The arginine residue is highly conserved (99/99 vertebrates, UCSC), and is located in the ROD 2 Ig-like domain 22 (PMID: 32112656). There is a small physicochemical difference between arginine and histidine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.006% (2/34,520 alleles) in the Latino/Admixed American population. To our knowledge, this variant has not been reported in the relevant scientific literature. It has been identified in an individual with hypertrophic cardiomyopathy (Shariant) and reported as a variant of uncertain significance and likely benign (ClinVar ID: 539333). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.659). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PP3.