ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.11311+5536A>G (rs145581345)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000172708 SCV000055086 likely benign not provided 2013-06-24 criteria provided, single submitter research
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000041047 SCV000064738 uncertain significance not specified 2014-07-09 criteria provided, single submitter clinical testing The Met4938Val variant in TTN has been identified by our laboratory in 1 Caucasi an adult with unspecified cardiomyopathy. This variant has also been identified in 0.13% (11/8600) of European American chromosomes by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS/; dbSNP rs145581345). Computational prediction tools and conservation analysis are limited or unavailable for this v ariant. In summary, additional studies are needed to fully assess the clinical s ignificance of the Met4938Val variant.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000172708 SCV000703210 uncertain significance not provided 2017-08-31 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000041047 SCV001160508 uncertain significance not specified 2019-05-11 criteria provided, single submitter clinical testing The TTN c.14812A>G; p.Met4938Val variant (rs145581345; ClinVar Variation ID: 47778) 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.Met4938Val 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). Herman DS et al. Truncations of titin causing dilated cardiomyopathy. N Engl J Med. 2012 Feb 16;366(7):619-28. Linke and Hamdani. Gigantic business: titin properties and function through thick and thin. Circ Res 2014; 114(6): 1052-1068.
GeneDx RCV000172708 SCV000238135 not provided not provided 2014-08-29 no assertion provided 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).
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000172708 SCV001551895 uncertain significance not provided no assertion criteria provided clinical testing The TTN p.Met4938Val variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs145581345) as “With Uncertain significance allele”. In ClinVar, there are conflicting interpretations of pathogenicity from four submitters: 2x uncertain significance (Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine and EGL Genetic Diagnostics, Eurofins Clinical Diagnostics), 1x likely benign (Biesecker Lab/Human Development Section, National Institutes of Health), and not provided (GeneDx). The variant was identified in control databases in 192 of 281816 chromosomes (1 homozygous) at a frequency of 0.000681 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 19 of 10342 chromosomes (freq: 0.001837), European (non-Finnish) in 145 of 128398 chromosomes (freq: 0.001129), Other in 7 of 7192 chromosomes (freq: 0.000973), African in 6 of 24944 chromosomes (freq: 0.000241), European (Finnish) in 5 of 25104 chromosomes (freq: 0.000199), South Asian in 5 of 30606 chromosomes (freq: 0.000163) and Latino in 5 of 35322 chromosomes (freq: 0.000142); it was not observed in the East Asian population. The variant occurs outside of the splicing consensus sequence however 2 of 4 in silico prediction software programs (SpliceSiteFinder and MaxEntScan) predict the creation of a new 3' splice site. The p.Met4938 residue is not conserved across mammals and other organisms and 3 of 3 computational analyses (PolyPhen-2, BLOSUM, and MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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