ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.102398T>C (p.Ile34133Thr)

gnomAD frequency: 0.00006  dbSNP: rs764179161
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000732211 SCV000860134 uncertain significance not provided 2018-03-15 criteria provided, single submitter clinical testing
Invitae RCV001307848 SCV001497276 uncertain significance Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2023-10-15 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 34133 of the TTN protein (p.Ile34133Thr). This variant is present in population databases (rs764179161, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with TTN-related conditions. ClinVar contains an entry for this variant (Variation ID: 596390). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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). 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 RCV002222619 SCV002500287 uncertain significance not specified 2022-03-09 criteria provided, single submitter clinical testing Variant summary: TTN c.94694T>C (p.Ile31565Thr) results in a non-conservative amino acid change located in the M-band region (100% PSI score, corresponding to a constitutively expressed exon) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 249066 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.94694T>C has been reported in the literature as a VUS in an asymptomatic (incidental) male with no FH of cardiomyopathy and an asymmetric septal pattern of hypertrophy who underwent whole genome analysis (WGS) following prior genetic testing on a 46 gene panel that had not established a molecular diagnosis (example, Bagnall_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Hypertrophic/Dilated Cardiomyopathy/Limb-Girdle Muscular Dystrophy, Type 2J. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Revvity Omics, Revvity Omics RCV000732211 SCV003819742 uncertain significance not provided 2022-08-22 criteria provided, single submitter clinical testing

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