Description
Variant summary: TTN c.61426C>T (p.Pro20476Ser) results in a non-conservative amino acid change located in the A-band region of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0036 in 247582 control chromosomes, predominantly at a frequency of 0.0055 within the Non-Finnish European subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 9 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Cardiomyopathy phenotype (0.00063), strongly suggesting that the variant is a benign polymorphism. c.61426C>T has been reported in the literature in association with multiple different Cardiomyopathy phenotypes including arrhythmogenic right ventricular cardiomyopathy, hypertrophic cardiomyopathy, sudden arrhythmic death syndrome, dilated cardiomyopathy, sudden unexplained death and long QT syndrome (e.g. Campuzano_2015, Hertz_2016, Lopes_2013, Nunn_2016). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign (n=8) and as uncertain significance (n=2). Based on the evidence outlined above, the variant was classified as benign.
| # | 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 |
