ClinVar Miner

Submissions for variant NM_001018005.2(TPM1):c.702+4A>G

dbSNP: rs730881145
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159382 SCV000209328 uncertain significance not provided 2011-12-08 criteria provided, single submitter clinical testing The c.702+4 A>G variant in the TPM1 gene has not been reported previously as a disease-causing mutation nor as a benign polymorphism, to our knowledge. Three in silico splice analysis programs predict c.702+4 A>G destroys or reduces the efficiency of the natural donor splice site of intron 7. This may lead to either an abnormal message, which is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. However, the majority of disease-causing mutations in the TPM1 gene are missense mutations and no splice site mutations have been reported in the TPM1 gene to date. The NHLBI Exome Variant Server reports c.702+4 A>G in the TPM1 gene was not observed in at least 6500 individuals from Caucasian and African American backgrounds. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in HCM panel(s).
Invitae RCV001340152 SCV001533951 uncertain significance Hypertrophic cardiomyopathy 2020-04-08 criteria provided, single submitter clinical testing 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. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with TPM1-related conditions. ClinVar contains an entry for this variant (Variation ID: 181672). This variant is not present in population databases (ExAC no frequency). This sequence change falls in intron 7 of the TPM1 gene. It does not directly change the encoded amino acid sequence of the TPM1 protein, but it affects a nucleotide within the consensus splice site of the intron.

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