ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.61409T>C (p.Ile20470Thr) (rs202012910)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000040443 SCV000064134 uncertain significance not specified 2012-11-07 criteria provided, single submitter clinical testing The Ile17902Thr variant in TTN has not been reported in the literature nor previ ously identified by our laboratory. This variant has been identified in 2/8304 E uropean American chromosomes and 2/3916 African American chromosomes from a broa d population by the NHLBI Exome Sequencing Project ( /EVS). Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. In summary, additional information is needed to fully ass ess the variant's clinical significance.
Genetic Services Laboratory, University of Chicago RCV000118773 SCV000153317 uncertain significance not provided 2014-01-10 criteria provided, single submitter clinical testing
GeneDx RCV000040443 SCV000237376 uncertain significance not specified 2017-09-06 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the TTN gene. The I18829T variant, also denoted as I17902T due to the use of an alternate transcript, has been reported in an individual who underwent targeted panel testing who also harbored a reportedly de novo variant in the SLC25A4 gene (LaDuca et al., 2017); however, this individual later underwent exome sequencing but no clinical details regarding the indication for the targeted panel testing and/or exome sequencing were described. The I18829T variant has also been observed in two individuals referred for cardiomyopathy genetic testing at GeneDx, although both individuals harbored additional cardiogenetic variants and no segregation data are available. Additionally, this variant has been observed in 6/9634 (0.06%) alleles from individuals of African ancestry, and 7/64296 (0.01%) alleles from individuals of Non-Finnish European ancestry, in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Nevertheless, I18829T is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Moreover, this substitution occurs at a position where only amino acids with similar properties to isoleucine (I) are tolerated across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, while this missense variant is located in the A-band region of titin, the majority of pathogenic variants in the TTN gene associated with DCM are truncating variants in this region (Herman et al., 2012).
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000118773 SCV000706525 uncertain significance not provided 2017-02-24 criteria provided, single submitter clinical testing
Ambry Genetics RCV000621098 SCV000736103 likely benign Cardiovascular phenotype 2020-05-20 criteria provided, single submitter clinical testing In silico models in agreement (benign);Subpopulation frequency in support of benign classification
Invitae RCV000643646 SCV000765333 uncertain significance Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2017-12-09 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000040443 SCV001362822 uncertain significance not specified 2019-11-11 criteria provided, single submitter clinical testing Variant summary: TTN c.53705T>C (p.Ile17902Thr) results in a non-conservative amino acid change located in the A-band region 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 0.00011 in 213576 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in TTN causing Dilated Cardiomyopathy (0.00011 vs 0.00063), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.53705T>C in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Four 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.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000118773 SCV001554280 uncertain significance not provided no assertion criteria provided clinical testing The TTN p.I17902T variant was not identified in the literature but was identified in dbSNP (ID: rs202012910) and ClinVar (classified as uncertain significance by Invitae, GeneDx and five other laboratories). The variant was identified in control databases in 30 of 244940 chromosomes at a frequency of 0.0001225 (Genome Aggregation Database March 6, 2019, v2.1.1). The p.I17902 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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