Submissions for variant NM_001267550.2(TTN):c.9487C>T (p.Arg3163Cys)

gnomAD frequency: 0.00031  dbSNP: rs140664731

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000040920	SCV000064611	uncertain significance	not specified	2017-08-10	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Arg3163Cys va riant in TTN has been identified by our laboratory in 2 adults with concentric L VH and atrial fibrillation. This variant has also been identified in 0.1% (23/24 028) of African chromosomes by the Genome Aggregation Database (gnomAD, http://g nomad.broadinstitute.org; dbSNP rs140664731). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary , while the clinical significance of the p.Arg3163Cys variant is uncertain, its frequency suggests that it is more likely to be benign.
GeneDx	RCV000786253	SCV000238061	likely benign	not provided	2020-06-09	criteria provided, single submitter	clinical testing
Invitae	RCV001088345	SCV000765152	likely benign	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-31	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000786253	SCV001475813	likely benign	not provided	2020-02-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002371852	SCV002685041	likely benign	Cardiovascular phenotype	2019-02-08	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Revvity Omics, Revvity	RCV000786253	SCV003822815	uncertain significance	not provided	2022-09-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000040920	SCV004020332	uncertain significance	not specified	2023-06-10	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003407412	SCV004113072	uncertain significance	TTN-related condition	2023-06-19	criteria provided, single submitter	clinical testing	The TTN c.9487C>T variant is predicted to result in the amino acid substitution p.Arg3163Cys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.11% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-179631324-G-A). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000786253	SCV004564491	uncertain significance	not provided	2023-03-28	criteria provided, single submitter	clinical testing	The TTN c.9487C>T; p.Arg3163Cys variant (rs140664731; ClinVar Variation ID: 47651) is rare in the general population (<0.2% 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.Arg3163Cys variant cannot be determined with certainty. References: Begay RL et al. Role of Titin Missense Variants in Dilated Cardiomyopathy. J Am Heart Assoc. 2015 Nov 13;4(11). PMID: 26567375. Herman DS et al. Truncations of titin causing dilated cardiomyopathy. N Engl J Med. 2012 Feb 16;366(7):619-28. PMID: 22335739. Linke WA and Hamdani N. Gigantic business: titin properties and function through thick and thin. Circ Res 2014; 114(6): 1052-1068. PMID: 24625729.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000786253	SCV000925003	uncertain significance	not provided	2017-09-05	no assertion criteria provided	provider interpretation	p.Arg3163Cys (c.9487C>T) in exon 41 of the TTN gene (NM_133378.4; 2:179631324) Given that the uncertain clinical significance of missense variants in TTN and this variant’s high frequency in the general population, we consider this variant a variant of uncertain significance, likely benign and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). It is unclear at this time what role, if any, TTN missense variants play in causing inherited cardiovascular disese. While truncating (nonsense, frameshift, etc.) variants in TTN have been implicated in dilated cardiomyopathy, the impact of missense variants in this gene remains unclear. In general population samples there is a high prevalence of rare or novel TTN missense variants, making it likely that testing anyone with this panel would uncover such a variant. As such we would generally consider all TTN missense variants to be variants of uncertain significance. The variant has been seen in at least 3 unrelated cases of heart disease (not including this patient's family). These are all cases from labs: -LMM has seen this variant in 2 adults, one with concentric LVH and another with atrial fibrillation. -This variant is reported in ClilnVar. GeneDx also classifies this variant as a variant of uncertain significance. -Per Cardiodb, this variant is "unlikely to be pathogenic" based on population frequency in large population databases. This variant has not been published in the literature. Per the test report, "computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity." The arginine at codon 3163 is completely conserved across species, and neighboring amino acids are well-conserved. Other nearby variants are classified as either (likely) benign or as variants of uncertain significance (Arg3163His, Gln3162Arg). The variant was reported online in 31 of 138,071 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 23 of 12,014 individuals of African descent (MAF=0.09%), 6 of 9,400 individuals of East Asian descent, 1 of 17,186 individuals of Latino descent and 1 of 62,943 individuals of European descent. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease.