Submissions for variant NM_001458.5(FLNC):c.3623C>T (p.Ala1208Val)

gnomAD frequency: 0.00009  dbSNP: rs202184162

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000545271	SCV000650995	likely benign	Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant	2024-01-15	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001198638	SCV001369632	uncertain significance	Hypertrophic cardiomyopathy 26	2019-10-10	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: No criteria apply.
GeneDx	RCV001569461	SCV001793543	likely benign	not provided	2021-04-28	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 30411535)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001198638	SCV002557043	uncertain significance	Hypertrophic cardiomyopathy 26	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. 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). (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to valine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (27 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (12 heterozygotes, 0 homozygotes). (I) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0600 - Variant is located in the annotated ROD1 domain Ig-like 10 (PMID: 32112656). (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. The p.(Ala1208Thr) variant has been identified in a control individual in a hypertrophic cardiomyopathy (HCM) cohort (PMID: 30411535) and has been reported as a VUS in ClinVar. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. It has been identified in an individual with HCM (PMID: 30411535) and in a control individual in a cohort study (PMID: 26555887). In addition, it has been reported both as likely benign (LOVD) and VUS (ClinVar, LOVD). (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	RCV002460091	SCV002617990	uncertain significance	Cardiovascular phenotype	2023-11-03	criteria provided, single submitter	clinical testing	The p.A1208V variant (also known as c.3623C>T), located in coding exon 21 of the FLNC gene, results from a C to T substitution at nucleotide position 3623. The alanine at codon 1208 is replaced by valine, an amino acid with similar properties. This alteration has been reported in a hypertrophic cardiomyopathy (HCM) cohort; however, clinical details were limited (Cui H et al. Mol Genet Genomic Med, 2018 11;6:1104-1113). 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.
Revvity Omics, Revvity	RCV001569461	SCV003833204	uncertain significance	not provided	2023-08-02	criteria provided, single submitter	clinical testing