ClinVar Genomic variation as it relates to human health

The p.A2430V variant (also known as c.7289C>T), located in coding exon 44 of the FLNC gene, results from a C to T substitution at nucleotide position 7289. The alanine at codon 2430 is replaced by valine, an amino acid with similar properties. This variant has been reported in individuals with hypertrophic cardiomyopathy (HCM) and, in one family, showed limited segregation with HCM and elevated creatine kinase (Valdés-Mas R et al. Nat Commun, 2014 Oct;5:5326; Gómez J et al. Circ Cardiovasc Genet, 2017 Apr;10; Schänzer A et al. J Muscle Res Cell Motil, 2021 06;42:381-397). This variant has also been detected in an individual from a control cohort; however, details were limited (Janssens J et al. Acta Neuropathol Commun, 2015 Nov;3:68). Studies of myocardial tissue from an affected individual with this variant and neonatal rat cardiomyocytes expressing this variant demonstrated abnormal protein aggregates (Valdés-Mas R et al. Nat Commun, 2014 Oct;5:5326; Schänzer A et al. J Muscle Res Cell Motil, 2021 06;42:381-397). This amino acid position is well 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.

Variant summary: FLNC c.7289C>T (p.Ala2430Val) results in a non-conservative amino acid change located in the 22nd filamin/ABP280 repeat (IPR001298, UniProt) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 246700 control chromosomes, predominantly at a frequency of 0.0002 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 18-fold of the estimated maximal expected allele frequency for a pathogenic variant in FLNC causing Cardiomyopathy phenotype (1.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.7289C>T has been reported in the literature in individuals affected with Hypertrophic Cardiomyopathy (e.g. Valdes-Mas_2014, Gomez_2017, Schanzer_2021), where in one family the variant seemed to segregate with the phenotype (Valdes-Mas_2014), and in another patient the cardiac histology was consistent with myofibrillar myopathy, but segregation analysis was not possible in this family (Schanzer_2021). These data indicate that the variant maybe be associated with disease. At least one publication reported experimental evidence evaluating an impact on protein function and demonstrated increased protein aggregation, and mislocalization to the perinuclear region in rat cardiac myoblasts transfected with the variant (Valdes-Mas_2014). The following publications have been ascertained in the context of this evaluation (PMID: 28356264, 31641117, 33710525, 25351925, 37937776). ClinVar contains an entry for this variant (Variation ID: 197502). Based on the evidence outlined above, the variant was classified as uncertain significance.

Reported in two probands with HCM; one of these probands also demonstrated elevated CK levels, and two out of three relatives who were heterozygous for A2430V demonstrated elevated CK levels and left ventricular wall measurements of 12 mm and 14 mm, respectively (Valdes-Mas et al., 2014; Gomez et al., 2017); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies suggest an effect on protein structure (Valdes-Mas et al., 2014); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 197502; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 26555887, 28356264, 25351925)