Description
Variant summary: ANKRD1 c.368C>T (p.Thr123Met) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00029 in 248014 control chromosomes, predominantly at a frequency of 0.00053 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 21 fold of the estimated maximal expected allele frequency for a pathogenic variant in ANKRD1 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.368C>T has been reported in the literature in at least one individual affected with Cardiomyopathy (e.g., Arimura_2009), however without strong evidence for causality. This report therefore does not provide unequivocal conclusions about association of the variant with Cardiomyopathy. At least two publications report experimental evidence evaluating an impact on protein function, suggesting that the variant may represent a gain-of-contractile-function mutation as it led to increased binding to I-band components and mislocalization to the nucleus, although the variant did incorporate correctly into the sarcomere (Arimura_2009, Crocini_2013). These findings do not allow convincing conclusions about the variant effect. The following publications have been ascertained in the context of this evaluation (PMID: 19608031, 23572067, 28518168). Ten ClinVar submitters (evaluation after 2014) have reported the variant with conflicting assessments (VUS, n = 9, likely benign, n = 1) citing overlapping evidence used in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely 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 |
