Description
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Pro426Leu (P426L; c.1277 C>T) in the TMPO gene We consider this a Variant of Unknown Significance (VUS)-Probably Benign, given that it has only been reported in the general population and not in any patients with cardiomyopathy. Furthermore, the TMPO gene has been associated in just one family with a disease of the heart muscle known as dilated cardiomyopathy (DCM). It might rightly be called a “gene of uncertain significance” given that only this one variant in one family has been reported: Arg690Cys in two brothers with DCM (Taylor et al. 2005; HGMD). That same variant, Arg690Cys, is present in the NHLBI Exome Sequencing Project (ESP) dataset in 4 Caucasian and 4 African-American individuals, raising the possibility that it is a rare benign variant. The specific variant found in our patient Pro426Leu, has not been reported in the scientific literature as a disease-causing mutation nor as a benign polymorphism to our knowledge. This is a conservative amino acid substitution in which a non-polar Proline is replaced by a non-polar Leucine at a residue that is conserved across species. In silico analysis with PolyPhen-2 predicts the variant to be “probably damaging” with a score of 1.0. The Pro426Leu variant has been observed in 16 out of ~7500 individuals from population datasets. It was found in 2 individuals from Finland in the 1000 Genomes data. It was also found in 13 Caucasian and 1 African-American individuals in the NHLBI Exome Sequencing Project (ESP) dataset, which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals (as of March 20, 2014). This represents an allele frequency of 0.15% among Caucasians in the ESP. The phenotype of the ESP individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension.
| # | Sample | Method | Observation |
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| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
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| 1 | germline | not provided | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |
