Submissions for variant NM_001267550.2(TTN):c.65782C>T (p.Arg21928Trp)

gnomAD frequency: 0.00004  dbSNP: rs371856109

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000221583	SCV000237435	uncertain significance	not specified	2017-01-27	criteria provided, single submitter	clinical testing	Missense variants in the TTN gene are considered 'unclassified' if they are not previously reported in the literature and do not have >1% frequency in the population to be considered a polymorphism. Research indicates that truncating mutations in the TTN gene are expected to account for approximately 25% of familial and 18% of sporadic idiopathic DCM; however, truncating variants in the TTN gene have been reported in approximately 3% of reported control alleles. There has been little investigation into non-truncating variants. (Herman D et al. Truncations of titin causing dilated cardiomyopathy. N Eng J Med 366:619-628, 2012) The variant is found in CARDIOMYOPATHY panel(s).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000221583	SCV000272725	uncertain significance	not specified	2015-07-07	criteria provided, single submitter	clinical testing	The p.Arg19360Trp variant in TTN has not been previously reported in individuals with cardiomyopathy, but has been identified in 1/9492 African chromosomes and 2/64022 European chromosomes by the Exome Aggregation Consortium (ExAC, http://e xac.broadinstitute.org; dbSNP rs371856109). Computational prediction tools and c onservation analysis do not provide strong support for or against an impact to t he protein. In summary, the clinical significance of the p.Arg19360Trp variant i s uncertain.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000547494	SCV000643536	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-04-11	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000733606	SCV000861694	uncertain significance	not provided	2018-06-13	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000768956	SCV000900329	uncertain significance	Cardiomyopathy	2016-09-07	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000733606	SCV001713229	uncertain significance	not provided	2019-08-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002354503	SCV002619962	uncertain significance	Cardiovascular phenotype	2020-05-06	criteria provided, single submitter	clinical testing	The p.R12863W variant (also known as c.38587C>T), located in coding exon 140 of the TTN gene, results from a C to T substitution at nucleotide position 38587. The arginine at codon 12863 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is highly 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	RCV000733606	SCV003824208	uncertain significance	not provided	2021-04-22	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000733606	SCV004229396	uncertain significance	not provided	2023-01-04	criteria provided, single submitter	clinical testing	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity (http://gnomad.broadinstitute.org). Computational tools disagree on the variant's effect on normal protein function.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000221583	SCV005886776	uncertain significance	not specified	2025-02-03	criteria provided, single submitter	clinical testing	Variant summary: TTN c.58078C>T (p.Arg19360Trp) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.3e-05 in 245500 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in TTN causing Dilated Cardiomyopathy (5.3e-05 vs 0.00039), allowing no conclusion about variant significance. c.58078C>T has been reported in the literature in at least one individual affected with Dilated Cardiomyopathy without evidence of causality (e.g. Mazzarotto_2020) . These report(s) do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 31983221). ClinVar contains an entry for this variant (Variation ID: 202797). Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004537551	SCV004727244	uncertain significance	TTN-related disorder	2023-12-20	no assertion criteria provided	clinical testing	The TTN c.65782C>T variant is predicted to result in the amino acid substitution p.Arg21928Trp. This variant was reported in an individual with dilated cardiomyopathy (Table S3, Mazzarotto et al. 2020. PubMed ID: 31983221). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.