Submissions for variant NM_001458.5(FLNC):c.643G>A (p.Val215Met)

gnomAD frequency: 0.00009  dbSNP: rs754309921

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000481861	SCV000574204	uncertain significance	not provided	2018-07-05	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the FLNC gene. The V215M variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed at a global allele frequency of 12/255438 (0.005%) in large population cohorts (Lek et al., 2016). The V215M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000663409	SCV000786697	uncertain significance	Distal myopathy with posterior leg and anterior hand involvement		criteria provided, single submitter	research	The heterozygous p.Val215Met variant was identified by our study in one individual with distal myopathy. This variant has not been reported in the literature, however it has been reported in ClinVar by by one clinical laboartory (ID: 424399). This variant has been identified in present in European (7/115,048), African (3/21,944), and East Asian (1/18,074) chromosomes at 0.01% by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs754309921). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Val215Met variant is uncertain.
Invitae	RCV000703450	SCV000832349	likely benign	Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant	2023-12-27	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765930	SCV000897350	uncertain significance	Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26	2018-10-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002367659	SCV002657432	uncertain significance	Cardiovascular phenotype	2024-01-18	criteria provided, single submitter	clinical testing	The p.V215M variant (also known as c.643G>A), located in coding exon 3 of the FLNC gene, results from a G to A substitution at nucleotide position 643. The valine at codon 215 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000481861	SCV003833116	uncertain significance	not provided	2019-01-15	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003419818	SCV004117330	uncertain significance	FLNC-related disorder	2023-04-13	criteria provided, single submitter	clinical testing	The FLNC c.643G>A variant is predicted to result in the amino acid substitution p.Val215Met. This variant was reported in an individual with limb-girdle weakness (Table S4, Töpf et al. 2020. PubMed ID: 32528171). This variant is reported in 0.0091% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-128477255-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Athena Diagnostics	RCV000481861	SCV004229640	uncertain significance	not provided	2022-09-27	criteria provided, single submitter	clinical testing	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. This variant has been seen where an alternate explanation for disease was also identified, suggesting this variant may not cause disease. Computational tools predict that this variant is damaging.