ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000007.13) (NC_000007.14)
Evidence for haploinsufficiency phenotype
PubMed ID Description
28008423 Begay et al 2016 reported a splice site variant (c.7251+1 G>A) in FLNC in two families with dilated cardiomyopathy detected by WES. In family 1, the variant was detected in all 3 affected individual who underwent testing and was absent from 3 out of 4 unaffected family members. The apparently unaffected carrier was 34 years old with a history of palpitations and an unremarkable echocardiogram but declined further follow-up. In the second family, the variant was detected in two affected individuals and absent in two unaffected individuals. Both families were from the same region of Italy suggesting a founder effect. Another splice site variant (c.5669-1delG) was detected in two affected family members in a third dilated cardiomyopathy family. The variant was shown to result in decreased FLNC RNA and protein levels in cardiac tissue.
27908349 Ortix-Genga et al 2016 sequenced a panel of 213 genes in 2,877 patients with inherited cardiovascular disease. They identified 23 different FLNC truncating variants in 28 unrelated probands. The phenotypes of individuals carrying FLNC truncating variants included dilated cardiomyopathy, arrhythmogenic cardiomyopathy, and restrictive cardiomyopathy. 121 relatives were clinically and genetically evaluated. Fifty-four relatives carried the FLNC variants identified in the probands. Cardiac alterations were found in 74% of relatives with the variant with a mean age of presentation in affected carriers of 41 years. Eleven of 12 healthy carriers were under the age of 40. None of the 67 noncarriers were clinically affected.
28436997 Janin et al 2017 sequenced 48 cardiomyopathy related genes in a cohort of 222 unrelated probands with dilated cardiomyopathy. Truncating variants in FLNC were detected in 10 patients. These variants were absent from databases of control individuals. Additionally, no truncating FLNC variants were detected in a cohort of 363 patients with hypertrophic cardiomyopathy.
30067491 Begay et al 2018 evaluated 319 dilated cardiomyopathy families using whole exome sequencing. A total of 6 FLNC loss of function variants in 7 families were identified including 2 nonsense, 1 frameshift and 3 splice site variants. RNA-seq was performed on cardiac tissue from one patient carrying a c.5669-1delG variant. The majority of reads (87%) were wildtype supporting a mechanism of nonsense mediated decay leading to haploinsufficiency.

Haploinsufficiency phenotype comments:

Variants in FLNC have been observed in individuals with various presentations, including dilated cardiomyopathy, myofibrillar myopathy, hypertrophic cardiomyopathy, etc. The evidence for haploinsufficiency in this review specifically pertains to dilated cardiomyopathy; other presentations may be caused by alternative genetic mechanisms.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity