Submissions for variant NM_001458.5(FLNC):c.5954C>T (p.Ser1985Leu)

gnomAD frequency: 0.00031  dbSNP: rs200415625

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000649090	SCV000770915	likely benign	Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant	2024-01-26	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000998922	SCV001155276	uncertain significance	not provided	2019-05-01	criteria provided, single submitter	clinical testing
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV001089626	SCV001245103	benign	Hypertrophic cardiomyopathy	2018-04-17	criteria provided, single submitter	research	This variant has been identified as part of our research program. Refer to the 'condition' field for the phenotype of the proband(s) identified with this variant. For further information please feel free to contact us.
GeneDx	RCV000998922	SCV001813069	likely benign	not provided	2020-03-04	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar as a variant of uncertain significance by another clinical laboratory (ClinVar Variant ID# 539362; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 32112656)
Ambry Genetics	RCV002358857	SCV002655391	uncertain significance	Cardiovascular phenotype	2023-08-28	criteria provided, single submitter	clinical testing	The p.S1985L variant (also known as c.5954C>T), located in coding exon 36 of the FLNC gene, results from a C to T substitution at nucleotide position 5954. The serine at codon 1985 is replaced by leucine, an amino acid with dissimilar properties. This variant has been detected in a hypertrophic cardiomyopathy cohort; however, details were limited (Verdonschot JAJ et al. Hum. Mutat., 2020 Jun;41:1091-1111). This variant has also been detected in a frontotemporal dementia control cohort; however, cardiovascular history was not provided (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.
Revvity Omics, Revvity	RCV000998922	SCV003833164	uncertain significance	not provided	2020-10-29	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003420136	SCV004118001	uncertain significance	FLNC-related disorder	2023-04-30	criteria provided, single submitter	clinical testing	The FLNC c.5954C>T variant is predicted to result in the amino acid substitution p.Ser1985Leu. This variant was reported as uncertain significance in a hypertrophic cardiomyopathy cohort (Verdonschot et al. 2020. PubMed ID: 32112656). This variant is reported in 0.035% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-128492756-C-T). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003486909	SCV004240663	uncertain significance	Cardiomyopathy	2022-10-05	criteria provided, single submitter	clinical testing