Description
Found in a 14 yo female with incomplete RBBB on EKG and a history of two syncopal episodes during exercise. Her echocardiogram and cardiac MRI were read as normal, and she has no known skeletal myopathy. p.Val601Ala (c.1802T>C) in the FLNC gene (NM_001458.4) Chromosome location 7:128481013 T / C Based on the information reviewed below, we classify this as a VUS, probably benign, concluding that there is not sufficient evidence for its pathogenicity to warrant using it for predictive genetic testing. This variant has not previously been reported in the literature in association with disease, according to the Invitae report. It is present, however, in population databases and is most common in individuals with Latino ancestry like our patient. This is a conservative amino acid change, resulting in the replacement of a nonpolar Valine with a nonpolar Alanine. Valine at this location is well conserved across ~100 vertebrate species for which we have data as are surrounding residues, which may support the functional importance of this region of the protein. There are no Likely Pathogenic or Pathogenic missense variants listed in ClinVar within 10 amino acids to either side. According to the Invitae report, algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant was reported in 9 individuals in the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. Specifically, the variant was observed in 7 out of 14,839 Latino individuals (for the highest allele frequency: 0.02%), and 2 non-Finnish Europeans. Our patient has Latino ancestry. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases.
| # | Sample | Method | Observation |
|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
|---|
| 1 | germline | unknown | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |
