Total submissions: 6
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Laboratory for Molecular 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. |
Gene |
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, |
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, |
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 |