ClinVar Miner

Submissions for variant NM_001018005.2(TPM1):c.389T>C (p.Ile130Thr) (rs727503517)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000152117 SCV000200801 uncertain significance not specified 2014-04-17 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The Ile130Thr v ariant in TPM1 has been identified by our laboratory in one individual with DCM (LMM-unpublished data) but was absent from large population studies. Isoleucine (Ile) at position 130 is highly conserved in mammals and across evolutionarily d istant species and the change to Threonine (Thr) was predicted to be pathogenic using a computational tool clinically validated by our laboratory. This tool's p athogenic prediction is estimated to be correct 94% of the time (Jordan 2011). Although the low frequency of this variant and the computational predictions su ggest that it may be pathogenic, additional studies are needed to fully assess i ts clinical significance.
Invitae RCV000549273 SCV000623803 uncertain significance Hypertrophic cardiomyopathy 2018-12-13 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 130 of the TPM1 protein (p.Ile130Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with TPM1-related disease. ClinVar contains an entry for this variant (Variation ID: 165566). A computational algorithm designed to assess the pathogenicity of variants in TPM1 with regard to hypertrophic cardiomyopathy predicted this sequence change to be deleterious. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000619274 SCV000737307 uncertain significance Cardiovascular phenotype 2017-09-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000786231 SCV000924972 uncertain significance not provided 2017-08-24 no assertion criteria provided provider interpretation TPM1, Exon 4, c.389T>C (p.Ile130Thr), heterozygous, Uncertain Significance We have seen this variant in one patient in our center with DCM and a family history of DCM. Given it is rare but with only minimal case data and no segregation data, we consider this variant a variant of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in at least one unrelated case of DCM (not including this patient's family). There is so segregation data. LMM has an entry in ClinVar, as a variant of uncertain significance and they note they have seen it in one patient with DCM. There is no variation at codon 130 listed in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. The average coverage at that site in gnomAD is >30x.

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