ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.12145C>T (p.Pro4049Ser) (rs201888760)

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Total submissions: 8
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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 RCV000172704 SCV000051258 likely benign not provided 2013-06-24 criteria provided, single submitter research
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000041086 SCV000064777 uncertain significance not specified 2012-03-20 criteria provided, single submitter clinical testing The Pro3811Ser variant in TTN has been identified in 1/6622 European American ch romosomes from a broad population by the NHLBI Exome Sequencing Project (http:// Conservation and computational tools are limited or unavailable for this variant. Additional information is needed to assess the cli nical significance of this variant.
Invitae RCV000560737 SCV000642654 uncertain significance Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2017-12-07 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000172704 SCV000701607 uncertain significance not provided 2017-05-16 criteria provided, single submitter clinical testing
GeneDx RCV000041086 SCV000731018 likely benign not specified 2017-05-09 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.
Athena Diagnostics Inc RCV000172704 SCV000844618 uncertain significance not provided 2018-02-20 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000172704 SCV001153104 uncertain significance not provided 2020-01-01 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000172704 SCV001552712 uncertain significance not provided no assertion criteria provided clinical testing The TTN p.Pro3878Ser variant was identified in 1 of 144 proband chromosomes (frequency: 0.0069) from an individual with dilated cardiomyopathy who also carried a TTN truncating mutation (Franaszczyk_2017_PMID:28045975). The variant was identified in dbSNP (ID: rs201888760) and ClinVar (classified as likely benign by Biesecker Lab and GeneDx and uncertain significance by Invitae, Athena Diagnostics Inc, Laboratory for Molecular Medicine and EGL Genetic Diagnostics). The variant was identified in control databases in 104 of 279690 chromosomes (1 homozygous) at a frequency of 0.0003718 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Ashkenazi Jewish in 11 of 10328 chromosomes (freq: 0.001065), Other in 7 of 7110 chromosomes (freq: 0.000985), European (non-Finnish) in 63 of 127606 chromosomes (freq: 0.000494), South Asian in 13 of 30594 chromosomes (freq: 0.000425), Latino in 6 of 35360 chromosomes (freq: 0.00017) and African in 4 of 24182 chromosomes (freq: 0.000165), but was not observed in the East Asian, or European (Finnish) populations. The p.Pro3878 residue has limited species conservation data and computational analyses (BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of 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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