Submissions for variant NM_001458.5(FLNC):c.1885C>T (p.Arg629Trp)

gnomAD frequency: 0.00006  dbSNP: rs759376455

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000823088	SCV000963930	likely benign	Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant	2024-01-13	criteria provided, single submitter	clinical testing
Molecular Genetics, Royal Melbourne Hospital	RCV002221253	SCV002498664	uncertain significance	Distal myopathy with posterior leg and anterior hand involvement	2023-03-30	criteria provided, single submitter	clinical testing	This sequence change is predicted to replace arginine with tryptophan at codon 629 of the FLNC protein (p.(Arg629Trp)). The arginine residue is highly conserved (100 vertebrates, UCSC), and is located in a beta strand in the filamin 4 repeat domain. There is a large physicochemical difference between arginine and tryptophan. The variant is present in a large population cohort at a frequency of 0.003% (rs759376455, 9/280,900 alleles, 0 homozygotes in gnomAD v2.1), and has been reported as a variant of uncertain significance (ClinVar, LOVD). It has not been reported in the relevant medical literature. Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.3.2, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PP3.
Revvity Omics, Revvity	RCV001579972	SCV003833601	uncertain significance	not provided	2022-07-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004029126	SCV005017691	uncertain significance	Cardiovascular phenotype	2024-02-26	criteria provided, single submitter	clinical testing	The p.R629W variant (also known as c.1885C>T), located in coding exon 12 of the FLNC gene, results from a C to T substitution at nucleotide position 1885. The arginine at codon 629 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV001579972	SCV001809239	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001579972	SCV001952238	uncertain significance	not provided		no assertion criteria provided	clinical testing