Submissions for variant NM_001458.5(FLNC):c.4413A>T (p.Gln1471His)

gnomAD frequency: 0.00003  dbSNP: rs765435961

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000649185	SCV000771010	uncertain significance	Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant	2023-12-13	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 1471 of the FLNC protein (p.Gln1471His). This variant is present in population databases (rs765435961, gnomAD 0.008%). This missense change has been observed in individual(s) with FLNC-related conditions (PMID: 36178741). ClinVar contains an entry for this variant (Variation ID: 539450). 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.
Phosphorus, Inc.	RCV001823742	SCV002073455	uncertain significance	not specified	2022-01-19	criteria provided, single submitter	clinical testing	This missense variant results in an amino acid substitution of glutamine with histidine at codon 1471 of the FLNC gene. The variant has an entry in ClinVar (539450) NM_001458.5 (FLNC): c.4413A>T (p.Gln1471His) and has occurred in GnomAD with a total MAF of 0.0037% and highest MAF of 0.0081% in the European population. This position is not conserved. In silico functional algorithms agreed, with PolyPhen calling it possibly damaging, and SIFT deleterious, but no functional studies were performed to confirm these predictions. The variant has not occurred in literature associated with disease. Considering that this is a rare variant, whose impact on the protein and association with disease are unknown, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002331238	SCV002632002	uncertain significance	Cardiovascular phenotype	2024-01-29	criteria provided, single submitter	clinical testing	The p.Q1471H variant (also known as c.4413A>T), located in coding exon 25 of the FLNC gene, results from an A to T substitution at nucleotide position 4413. The glutamine at codon 1471 is replaced by histidine, an amino acid with highly similar properties. 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.
GeneDx	RCV003319390	SCV004023623	uncertain significance	not provided	2023-02-01	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge