ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.106927G>A (p.Val35643Ile) (rs754459138)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000727495 SCV000237967 likely benign not provided 2018-03-15 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000727495 SCV000709131 uncertain significance not provided 2017-06-06 criteria provided, single submitter clinical testing
Ambry Genetics RCV000618422 SCV000737312 likely benign Cardiovascular phenotype 2020-09-10 criteria provided, single submitter clinical testing In silico models in agreement (benign);Subpopulation frequency in support of benign classification
Invitae RCV001300616 SCV001489762 uncertain significance Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2020-08-25 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 35643 of the TTN protein (p.Val35643Ile). There is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs754459138, ExAC 0.03%). This variant has not been reported in the literature in individuals with TTN-related disease. ClinVar contains an entry for this variant (Variation ID: 203108). This variant is located in the M band of TTN (PMID: 25589632). Variants in this region may be relevant for neuromuscular disorders, but have not been definitively shown to cause cardiomyopathy (PMID: 23975875). Algorithms developed to predict the effect of missense changes on protein structure and function are unavailable for the TTN gene. The isoleucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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