Submissions for variant NM_001458.5(FLNC):c.140A>G (p.Asn47Ser)

gnomAD frequency: 0.00004  dbSNP: rs770861991

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000798884	SCV000938523	uncertain significance	Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 47 of the FLNC protein (p.Asn47Ser). This variant is present in population databases (rs770861991, gnomAD 0.004%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (Invitae). ClinVar contains an entry for this variant (Variation ID: 644893). 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.
GeneDx	RCV001731932	SCV001983874	uncertain significance	not provided	2021-10-11	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 644893; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 26582918)
Ambry Genetics	RCV002388463	SCV002699231	uncertain significance	Cardiovascular phenotype	2023-05-25	criteria provided, single submitter	clinical testing	The p.N47S variant (also known as c.140A>G), located in coding exon 1 of the FLNC gene, results from an A to G substitution at nucleotide position 140. The asparagine at codon 47 is replaced by serine, an amino acid with highly similar properties. 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.
CeGaT Center for Human Genetics Tuebingen	RCV001731932	SCV004161021	uncertain significance	not provided	2023-05-01	criteria provided, single submitter	clinical testing	FLNC: PP2
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003486930	SCV004240610	uncertain significance	Cardiomyopathy	2023-04-28	criteria provided, single submitter	clinical testing