ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.9487C>T (p.Arg3163Cys) (rs140664731)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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; 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; Limb-girdle muscular dystrophy, type 2J 2020-09-20 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000786253 SCV001475813 likely benign not provided 2020-02-19 criteria provided, single submitter clinical testing
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;, 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.

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