ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.102214T>C (p.Trp34072Arg) (rs375159973)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000472652 SCV000542991 uncertain significance Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2017-04-26 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with arginine at codon 34072 of the TTN protein (p.Trp34072Arg). The tryptophan residue is conserved and there is a moderate physicochemical difference between tryptophan and arginine. This variant is present in population databases (rs375159973, ExAC 0.003%). This variant has been observed on the opposite chromosome (in trans) from another variant (c.9388+1G>C) in an individual affected with congenital core myopathy combined with primary heart disease (PMID: 24105469). This variant is located within the M-band of TTN. Experimental studies have shown that this missense change reduced stability of interaction with serine–threonine kinase domain (TK) ligands, and did not detect catalytic activity of the mutant enzyme suggesting the mutation causes a complete loss of function of TK (PMID: 24105469). In summary, this variant is a rare missense change that has been shown to have a deleterious impact on protein function. It is located in the M-band of TTN and missense variants in this region are typically not causative for cardiac disease, but may be relevant for neuromuscular disorders. It has been reported in both the population and affected individuals, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
OMIM RCV000490792 SCV000579358 pathogenic Myopathy, early-onset, with fatal cardiomyopathy 2017-06-07 no assertion criteria provided literature only

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