Submissions for variant NM_001458.5(FLNC):c.6041T>C (p.Val2014Ala)

gnomAD frequency: 0.00002  dbSNP: rs765064363

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001042923	SCV001206632	uncertain significance	Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 2014 of the FLNC protein (p.Val2014Ala). This variant is present in population databases (rs765064363, gnomAD 0.005%). This missense change has been observed in individual(s) with frontotemporal dementia (PMID: 26555887). ClinVar contains an entry for this variant (Variation ID: 840829). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FLNC protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Baylor Genetics	RCV001333945	SCV001526661	uncertain significance	Hypertrophic cardiomyopathy 26	2018-07-09	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
GeneDx	RCV001759746	SCV001987718	uncertain significance	not provided	2022-09-15	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign in association with an FLNC-related disorder to our knowledge; This variant is associated with the following publications: (PMID: 26555887)
Ambry Genetics	RCV002355006	SCV002656725	uncertain significance	Cardiovascular phenotype	2019-12-19	criteria provided, single submitter	clinical testing	The p.V2014A variant (also known as c.6041T>C), located in coding exon 37 of the FLNC gene, results from a T to C substitution at nucleotide position 6041. The valine at codon 2014 is replaced by alanine, an amino acid with similar properties. This variant has been detected in a frontotemporal dementia cohort (Janssens J et al. Acta Neuropathol Commun, 2015 Nov;3:68). This amino acid position is 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001333945	SCV002766711	uncertain significance	Hypertrophic cardiomyopathy 26	2020-05-25	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v0.6.1, this variant is classified as 3B-VUS. Following criteria are met: 0103 - Both loss and gain of function are known mechanism of disease for this gene (PMID:23109048). 0107 - This gene is known to be associated with autosomal dominant disease. 0112 - Variants in this gene are known to have reduced penetrance. Reduced penetrance has been reported in families with familial hypertrophic cardiomyopathy (OMIM). 0200 - Variant is predicted to result in a missense amino acid change from valine to alanine (exon 37). 0302 - Variant is present in gnomAD >=0.0002 and <0.001 for dominant indication (6 heterozygotes, 0 homozygotes). 0309 - An alternative amino acid change at the same position has been observed in gnomAD (p.(Val2014Met): 7 heterozygotes, 0 homozygotes). 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. 0600 - Variant is located in an annotated domain or motif that does not have a well established function (Filamin repeat 18 domain; UniProt). 0705 - No comparable variants in relevant codon/region have previous evidence for pathogenicity. A different variant in the same codon resulting in a change to a methionine has been reported as uncertain clinical significance (ClinVar). 0807 - Variant has not previously been reported in individuals with myopathy or cardiomyopathy, however it has been reported in a patient with frontotemporal dementia without myopathy (PMID:26555887). 0905 - No published segregation evidence has been identified for this variant. 1007 - No published functional evidence has been identified for this variant. 1205 - Variant is maternally inherited.