ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.93674T>C (p.Ile31225Thr)

gnomAD frequency: 0.00003  dbSNP: rs727505175
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000156657 SCV000206378 uncertain significance not specified 2014-07-09 criteria provided, single submitter clinical testing The Ile28657Thr variant in TTN has not been reported in individuals with cardiom yopathy or in large population studies. Computational prediction tools and conse rvation analysis do not provide strong support for or against an impact to the p rotein. In summary, the clinical significance of the Ile28657Thr variant is unc ertain.
GeneDx RCV000156657 SCV000237778 uncertain significance not specified 2014-08-29 criteria provided, single submitter clinical testing Missense variants in the TTN gene are considered 'unclassified' if they are not previously reported in the literature and do not have >1% frequency in the population to be considered a polymorphism. Research indicates that truncating mutations in the TTN gene are expected to account for approximately 25% of familial and 18% of sporadic idiopathic DCM; however, truncating variants in the TTN gene have been reported in approximately 3% of reported control alleles. There has been little investigation into non-truncating variants. (Herman D et al. Truncations of titin causing dilated cardiomyopathy. N Eng J Med 366:619-628, 2012) The variant is found in CARDIOMYOPATHY panel(s).
Invitae RCV000642822 SCV000764509 uncertain significance Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2020-04-21 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 31225 of the TTN protein (p.Ile31225Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs727505175, ExAC 0.002%). This variant has been reported in an individual with sudden death and possible coronary artery disease on autopsy (PMID: 25500949). This variant is also known as c.66479T>C (p.Ile22160Thr) in the literature, ClinVar contains an entry for this variant (Variation ID: 179857). This variant is located in the A band of TTN (PMID: 25589632). Variants in this region may be relevant for cardiac or neuromuscular disorders (PMID: 25589632, 23975875). Algorithms developed to predict the effect of missense changes on protein structure and function are unavailable for the TTN gene. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000156657 SCV003934153 uncertain significance not specified 2023-05-23 criteria provided, single submitter clinical testing Variant summary: TTN c.85970T>C (p.Ile28657Thr) results in a non-conservative amino acid change located in the A-band region of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 248706 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.85970T>C has been reported in the literature in one individual with Sudden Unexplained Death (Narula_2015). This report does not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 25500949). One ClinVar submitter has assessed the variant since 2014: the variant was classified as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Mayo Clinic Laboratories, Mayo Clinic RCV003480067 SCV004225786 uncertain significance not provided 2022-07-12 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000157563 SCV000207309 uncertain significance Cardiomyopathy 2014-06-23 no assertion criteria provided clinical testing

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