Submissions for variant NM_001267550.2(TTN):c.104000T>C (p.Ile34667Thr)

gnomAD frequency: 0.00006  dbSNP: rs727504476

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000155604	SCV000205312	uncertain significance	not specified	2013-04-02	criteria provided, single submitter	clinical testing	The Ile32099Thr variant in TTN has been identified by our laboratory in 1 infant with DCM (LMM unpublished data). This variant has not been identified in large European American and African American populations by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/), though it may be present in other populations. Computational analyses (biochemical amino acid properties, conserva tion, AlignGVGD, and PolyPhen2) suggest that the Ile32099Thr variant may not imp act the protein, though this information is not predictive enough to rule out pa thogenicity. Additional information is needed to fully assess the clinical signi ficance of this variant.
Eurofins Ntd Llc (ga)	RCV000725227	SCV000335148	uncertain significance	not provided	2015-09-15	criteria provided, single submitter	clinical testing
Invitae	RCV000474904	SCV000542931	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2022-11-03	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 34667 of the TTN protein (p.Ile34667Thr). This variant is present in population databases (rs727504476, gnomAD 0.009%). 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: 178832). 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.
Fulgent Genetics, Fulgent Genetics	RCV000764296	SCV000895315	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J; Tibial muscular dystrophy; Myopathy, myofibrillar, 9, with early respiratory failure; Early-onset myopathy with fatal cardiomyopathy; Hypertrophic cardiomyopathy 9	2018-10-31	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000768831	SCV000900204	uncertain significance	Cardiomyopathy	2020-08-04	criteria provided, single submitter	clinical testing
GeneDx	RCV000725227	SCV001820641	likely benign	not provided	2019-06-18	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 28771489)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000155604	SCV002571820	uncertain significance	not specified	2022-08-06	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002399551	SCV002674223	uncertain significance	Cardiovascular phenotype	2020-08-18	criteria provided, single submitter	clinical testing	The p.I25602T variant (also known as c.76805T>C), located in coding exon 185 of the TTN gene, results from a T to C substitution at nucleotide position 76805. The isoleucine at codon 25602 is replaced by threonine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000725227	SCV003820297	uncertain significance	not provided	2019-12-26	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000725227	SCV004183803	uncertain significance	not provided	2023-11-01	criteria provided, single submitter	clinical testing	TTN: PM2