Submissions for variant NM_001267550.2(TTN):c.87448A>T (p.Ile29150Leu)

gnomAD frequency: 0.00022  dbSNP: rs189030321

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000458141	SCV000543152	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2016-05-12	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000618964	SCV000736597	uncertain significance	Cardiovascular phenotype	2020-03-04	criteria provided, single submitter	clinical testing	The p.I20085L variant (also known as c.60253A>T), located in coding exon 155 of the TTN gene, results from an A to T substitution at nucleotide position 60253. The isoleucine at codon 20085 is replaced by leucine, an amino acid with highly 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.
Eurofins Ntd Llc (ga)	RCV000727768	SCV000855158	uncertain significance	not provided	2018-06-28	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765552	SCV000896867	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
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001001980	SCV001159788	uncertain significance	not specified	2018-07-18	criteria provided, single submitter	clinical testing	The TTN c.79744A>T; p.Ile26582Leu variant is rare in the general population (<1% allele frequency in the Genome Aggregation Database) and has not been reported in the medical literature in association with dilated cardiomyopathy (DCM) or other TTN-related disease. The clinical relevance of rare missense variants in this gene, which are identified on average once per individual sequenced in affected populations (Herman 2012), is not well understood. Yet, evidence suggests that the vast majority of such missense variants do not contribute to the clinical outcome of DCM (Begay 2015). Thus, the clinical significance of the p.Ile26582Leu variant cannot be determined with certainty. References: Begay et al. Role of Titin Missense Variants in Dilated Cardiomyopathy. J Am Heart Assoc. 2015 Nov 13;4(11). pii: e002645 Herman et al. Truncations of Titin Causing Dilated Cardiomyopathy. N Engl J Med. 2012 Feb 16;366(7):619-28.
GeneDx	RCV000727768	SCV001785852	likely benign	not provided	2021-07-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001001980	SCV002041793	likely benign	not specified	2021-11-01	criteria provided, single submitter	clinical testing	Variant summary: TTN c.79744A>T (p.Ile26582Leu) results in a conservative amino acid change located in the A-band region of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00025 in 150984 control chromosomes, predominantly at a frequency of 0.002 within the Latino subpopulation in the gnomAD database (gnomAD v3.1, genomes dataset). The observed variant frequency within Latino control individuals in the gnomAD database is approximately 5-fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy phenotype (0.00039), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. To our knowledge, no occurrence of c.79744A>T in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (n=5) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Revvity Omics, Revvity	RCV000727768	SCV003823603	uncertain significance	not provided	2020-11-07	criteria provided, single submitter	clinical testing