ClinVar Miner

Submissions for variant NM_000364.4(TNNT2):c.711-4G>T (rs201753429)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000036612 SCV000060267 likely benign not specified 2015-05-07 criteria provided, single submitter clinical testing c.690-4G>T in intron 13 of TNNT2: This variant is not expected to have clinical significance because it is not located within the splice consensus sequence. It has been identified in 14/66732 European chromosomes by the Exome Aggregation Co nsortium (ExAC, http://exac.broadinstitute.org; dbSNP rs201753429).
Blueprint Genetics RCV000208300 SCV000264256 uncertain significance Sudden cardiac death 2015-10-22 criteria provided, single submitter clinical testing
Invitae RCV000468624 SCV000554784 likely benign not provided 2019-02-25 criteria provided, single submitter clinical testing
Color RCV000771268 SCV000903390 likely benign Cardiomyopathy 2018-08-25 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000036612 SCV000920312 uncertain significance not specified 2018-08-20 criteria provided, single submitter clinical testing Variant summary: TNNT2 c.690-4G>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00015 in 277154 control chromosomes in the gnomAD database, including 1 homozygote. Though it is relatively frequent, this frequency is not higher than expected for a pathogenic variant in TNNT2 causing Cardiomyopathy (0.00015 vs 0.00018). c.690-4G>T has been reported in the literature in individuals affected with Cardiomyopathy. 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. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with conflicting interpretations, including VUS (1x) and likely benign (2x). An internal sample with this variant also carried a pathogenic mutation in MYBPC3 variant (c.2373dupG), suggesting the variant of interest is likely not the cause of disease in this case and may be in the benign spectrum. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

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