ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.11311+4088A>G (rs142304137)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000041022 SCV000064713 uncertain significance not specified 2013-08-27 criteria provided, single submitter clinical testing The Lys4455Arg variant in TTN has been identified by our laboratory in 1 Caucasi an individual with LVNC and bidirectional VT and has been identified in 1/8588 E uropean American chromosomes by the NHLBI Exome Sequencing Project (http://evs.g s.washington.edu/EVS/; dbSNP rs142304137). Computational analyses are limited or unavailable for this variant. Additional information is needed to fully assess its clinical significance.
GeneDx RCV000041022 SCV000238116 likely benign not specified 2017-10-19 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000415195 SCV000492708 uncertain significance Syncope; Hypertrophic cardiomyopathy 2015-10-29 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000726846 SCV000703597 uncertain significance not provided 2018-05-22 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000726846 SCV001153134 uncertain significance not provided 2019-11-01 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001198289 SCV001369170 uncertain significance Tibial muscular dystrophy 2016-01-01 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000726846 SCV001552805 uncertain significance not provided no assertion criteria provided clinical testing The TTN p.Lys4455Arg variant was identified in the literature, however the frequency of this variant in an affected population was not provided. The variant was also identified in dbSNP (ID: rs142304137), ClinVar (conflicting interpretations of pathogenicity, associated with syncope and hypertrophic cardiomyopathy; classified as Uncertain Significance by Laboratory for Molecular Medicine at Partners Healthcare, Centre for Mendelian Genomics at University Medical Centre Ljubljana, EGL Genetic Diagnostics and classified as Likely Benign by GeneDx), and LOVD 3.0. The variant was not identified in the Cosmic database. The variant was identified in control databases in 110 of 280462 chromosomes at a frequency of 0.000392 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: South Asian in 30 of 30546 chromosomes (freq: 0.000982), European (non-Finnish) in 62 of 128212 chromosomes (freq: 0.000484), Other in 3 of 7108 chromosomes (freq: 0.000422), Latino in 13 of 35210 chromosomes (freq: 0.000369), African in 2 of 24318 chromosomes (freq: 0.000082), while the variant was not observed in the Ashkenazi Jewish, East Asian, and European (Finnish) populations. The variant was identified in a 5 year old asymptomatic female who presented with sinus bradycardia and was found to have exercise-induced bidirectional VT and a hypertrabeculated left ventricle (Egan_2013_PMID: 23476865). A pan cardiomyopathy microarray identified three missense variants in this individual: RYR2 p.Arg169Gln, CASQ2 p.Asp398del, and TTN p.Lys4455Arg (Egan_2013_PMID: 23476865). Four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE) predict a greater than 10% difference in splicing, specificically a decrease in 5’ splicing activity at the variant location. However, this information is not predictive enough to assume 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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