Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000694056 | SCV000822483 | likely benign | Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant | 2023-11-28 | criteria provided, single submitter | clinical testing | |
Ce |
RCV003144524 | SCV002062785 | likely benign | not provided | 2023-12-01 | criteria provided, single submitter | clinical testing | FLNC: BP4 |
Victorian Clinical Genetics Services, |
RCV002272333 | SCV002557072 | uncertain significance | Primary dilated cardiomyopathy | 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-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). (I) 0200 - Variant is predicted to result in a missense amino acid change from methionine to valine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (31 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated filamin domain (NCBI). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported once as VUS in ClinVar without clear phenotype and also has been seen in a control subject in a HCM study (PMID: 28356264). (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 | RCV002458245 | SCV002739703 | uncertain significance | Cardiovascular phenotype | 2024-01-10 | criteria provided, single submitter | clinical testing | The p.M370V variant (also known as c.1108A>G), located in coding exon 7 of the FLNC gene, results from an A to G substitution at nucleotide position 1108. The methionine at codon 370 is replaced by valine, an amino acid with highly similar properties. This variant has been reported in frontotemporal dementia cohorts and in one control individual from a hypertrophic cardiomyopathy study; however, details of cardiovascular history were limited for these individuals (Janssens J et al. Acta Neuropathol Commun, 2015 Nov;3:68; Gómez J et al. Circ Cardiovasc Genet, 2017 Apr;10; Blauwendraat C et al. Genet Med, 2018 02;20:240-249). 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, |
RCV003144524 | SCV003831454 | uncertain significance | not provided | 2019-08-14 | criteria provided, single submitter | clinical testing |