ClinVar Genomic variation as it relates to human health

The p.D1691N variant (also known as c.5071G>A), located in coding exon 30 of the FLNC gene, results from a G to A substitution at nucleotide position 5071. The aspartic acid at codon 1691 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been reported as de novo in a subject with skeletal myopathy (Zhang YT et al. Chin. Med. J., 2018 Dec;131:2986-2988). This variant has also been detected in a hypertrophic cardiomyopathy genetic testing case, and cases with noncompaction and/or dilated cardiomyopathy (van Lint FHM et al. Neth Heart J. 2019 Jun;27(6):304-309; Shumkova M. Kardiol Pol. 2021 May;79(6):716-717; Ware SM. Am J Hum Genet. 2022 Feb;109(2):282-298). This amino acid position is highly 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.

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1691 of the FLNC protein (p.Asp1691Asn). This variant is present in population databases (rs777061037, gnomAD 0.02%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with hypertrophic cardiomyopathy, left ventricular non-compaction, and/or myofibrillar myopathy (PMID: 30539912, 30847666, 33890751). ClinVar contains an entry for this variant (Variation ID: 570701). 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.

Variant summary: FLNC c.5071G>A (p.Asp1691Asn) results in a conservative amino acid change located in the Ig-like 15 region (Verdonschot_2020) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 249602 control chromosomes (gnomAD). The observed variant frequency is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant in FLNC causing Dilated Cardiomyopathy phenotype (7.8e-06), strongly suggesting that the variant is benign. c.5071G>A has been reported in the literature in individuals affected with Limb-girdle muscular dystrophies, Filamin C Myopathy, Hypertrophic cardiomyopathy or Left ventricular noncompaction cardiomyopathy, including one de novo occurrence (Aurino_2008, Zhang_2018, van Lint_2019, Shumkova_2021). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 19472918, 33890751, 32112656, 30539912, 30847666). ClinVar contains an entry for this variant (Variation ID: 570701). Based on the evidence outlined above, the variant was classified as uncertain significance.

FLNC: PP3