Submissions for variant NM_001458.5(FLNC):c.6889G>A (p.Val2297Met)

gnomAD frequency: 0.00001  dbSNP: rs1420394583

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000794895	SCV000934330	pathogenic	Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant	2023-12-28	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 2297 of the FLNC protein (p.Val2297Met). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with restrictive cardiomyopathy (PMID: 29212899, 29650767, 30418145, 31245841; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 641618). 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) performed at Invitae indicates that this missense variant is not expected to disrupt FLNC protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects FLNC function (PMID: 29212899). For these reasons, this variant has been classified as Pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001268782	SCV001447963	likely pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
GeneDx	RCV001268782	SCV001771654	likely pathogenic	not provided	2023-05-04	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect that includes reduced contractile activity when compared with control cells (Tucker et al., 2017); however, additional studies are needed to validate the functional effect of this variant in vivo; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31245841, 32154132, 30260051, 32824180, 33429969, 29212899, 29212901, 29650767, 30418145, 32295012, 32112656, 30919686, 29858533, 35345275, 33557094, 33802723, 36935760, 36104822, 34971933, 35456187, 35159226, 36560844)
Ambry Genetics	RCV003166124	SCV003859319	uncertain significance	Cardiovascular phenotype	2022-12-19	criteria provided, single submitter	clinical testing	The p.V2297M variant (also known as c.6889G>A), located in coding exon 41 of the FLNC gene, results from a G to A substitution at nucleotide position 6889. The valine at codon 2297 is replaced by methionine, an amino acid with highly similar properties. This alteration has been reported in individuals with restrictive cardiomyopathy (RCM), including one individual with RCM and myopathy, and was seen to segregate with disease (Tucker NR et al. Circ Cardiovasc Genet, 2017 Dec;10:[ePub ahead of print]; Ader F et al. Med Sci (Paris), 2018 Nov;34 Hors série n°2:39-41; Ma Y et al. Circ Genom Precis Med, 2018 Apr;11:e002117; Roldán-Sevilla A et al. Circ Genom Precis Med, 2019 Mar;12:e002388; Xiao F et al. Transl Pediatr, 2020 Feb;9:21-33; Muravyev A et al. Orphanet J Rare Dis, 2022 Sep;17:358). In vitro studies showed this alteration may impact protein function (Tucker NR et al. Circ Cardiovasc Genet, 2017 Dec;10:[ePub ahead of print]). 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.