ClinVar Miner

Submissions for variant NM_003276.2(TMPO):c.1277C>T (p.Pro426Leu) (rs141443652)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000172597 SCV000051428 likely benign not provided 2013-06-24 criteria provided, single submitter research
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001283631 SCV000605387 likely benign none provided 2019-10-02 criteria provided, single submitter clinical testing
GeneDx RCV000223911 SCV000616896 likely benign not specified 2017-12-06 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV001081032 SCV000646392 likely benign Loeys-Dietz syndrome 2 2020-11-06 criteria provided, single submitter clinical testing
Phosphorus, Inc. RCV000578085 SCV000679888 uncertain significance Primary dilated cardiomyopathy 2017-08-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV000618908 SCV000737175 likely benign Cardiovascular phenotype 2018-11-12 criteria provided, single submitter clinical testing Other strong data supporting benign classification;Subpopulation frequency in support of benign classification
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000625188 SCV000744068 likely benign Dilated cardiomyopathy 1T 2016-05-26 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000625188 SCV000745517 likely benign Dilated cardiomyopathy 1T 2015-09-21 criteria provided, single submitter clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000852682 SCV000995391 benign Arrhythmogenic right ventricular cardiomyopathy; Amyloidosis 2018-07-13 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000223911 SCV000280495 uncertain significance not specified 2014-03-20 no assertion criteria provided clinical testing 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.

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