ClinVar

Description

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.