Submissions for variant NM_001458.5(FLNC):c.2491G>A (p.Val831Ile)

gnomAD frequency: 0.00003  dbSNP: rs746478952

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000649170	SCV000770995	uncertain significance	Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 831 of the FLNC protein (p.Val831Ile). This variant is present in population databases (rs746478952, gnomAD 0.004%). This missense change has been observed in individuals with FLNC-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 539436). 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.
Ambry Genetics	RCV002424506	SCV002741025	uncertain significance	Cardiovascular phenotype	2021-11-22	criteria provided, single submitter	clinical testing	The p.V831I variant (also known as c.2491G>A), located in coding exon 16 of the FLNC gene, results from a G to A substitution at nucleotide position 2491. The valine at codon 831 is replaced by isoleucine, an amino acid with highly similar properties. This variant has been detected in an individual with frontotemporal dementia (Janssens J et al. Acta Neuropathol Commun, 2015 Nov;3:68). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Clinical Genetics, Academic Medical Center	RCV001701427	SCV001917690	uncertain significance	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001701427	SCV001963313	uncertain significance	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001701427	SCV002035652	uncertain significance	not provided		no assertion criteria provided	clinical testing