ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.95270T>C (p.Ile31757Thr) (rs72648259)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000082452 SCV000054882 uncertain significance not provided 2013-06-24 criteria provided, single submitter research
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000082452 SCV000114481 uncertain significance not provided 2018-05-31 criteria provided, single submitter clinical testing
GeneDx RCV000082452 SCV000237803 uncertain significance not provided 2018-08-16 criteria provided, single submitter clinical testing The I30116T variant of uncertain significance in the TTN gene, also denoted as I22692T and I31757T due to the use of alternate transcripts, has been previously reported in association with cardiomyopathy (Lopes et al., 2013; Begay et al., 2015). Lopes et al. (2013) identified I30116T in two unrelated individuals with HCM who both harbored additional variants in the TTN gene, as well as in other genes. Subsequently, Begay et al. (2015) reported this variant in two unrelated individuals with DCM, one of whom also harbored a second variant in the TTN gene. This variant has also been observed both independently, and in conjunction with additional cardiogenetic variants, in multiple individuals referred for cardiomyopathy genetic testing at GeneDx. However, for these reported cases and cases observed at GeneDx, no informative segregation data is available to further clarify the role of this variant in disease. Moreover, I30116T was observed in one individual from a cohort of individuals not selected for cardiomyopathy, arrhythmia or family history of sudden cardiac death who underwent exome sequencing (Ng et al., 2013). It has also been observed in 77/126,162 (0.06%) alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016).Nevertheless, the I30116T variant is a non-conservative amino acid substitution, which is likely to impact secondaryprotein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurswithin the 119th fibronectin domain in the A-band region of titin, at a position that is conserved across species. Insilico analysis predicts this variant is probably damaging to the protein structure/function. However, althoughI30116T is located in the A-band region of titin, the majority of pathogenic variants in the TTN gene associated withDCM are truncating variants in the A-band region (Herman et al., 2012).
Illumina Clinical Services Laboratory,Illumina RCV000312560 SCV000420685 uncertain significance Limb-Girdle Muscular Dystrophy, Recessive 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000369634 SCV000420686 uncertain significance Distal myopathy Markesbery-Griggs type 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000277450 SCV000420687 uncertain significance Hypertrophic cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000317322 SCV000420688 uncertain significance Hereditary myopathy with early respiratory failure 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000355719 SCV000420689 uncertain significance Dilated Cardiomyopathy, Dominant 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000263196 SCV000420690 uncertain significance Myopathy, early-onset, with fatal cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000465970 SCV000542824 uncertain significance Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2018-01-03 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000154888 SCV000204570 uncertain significance not specified 2013-09-20 criteria provided, single submitter clinical testing The Ile29189Thr variant in TTN has now been identified by our laboratory in 2 in dividuals with cardiomyopathy (1 child with WPW and clinical features of Danon d isease and 1 infant with cardiomyopathy). It has also been identified in 2/8370 European American chromosomes by the NHLBI Exome Sequencing Project (http://evs. gs.washington.edu/EVS/; dbSNP rs72648259). Computational analyses (biochemical a mino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provi de strong support for or against an impact to the protein. At this time, additio nal information is needed to fully assess the clinical significance of this vari ant.

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