ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.64903C>T (p.Arg21635Cys) (rs201614524)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000040485 SCV000064176 uncertain significance not specified 2012-10-08 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The Arg19067Cys var iant in TTN has been identified in 2/8240 European American chromosomes from a b road population by the NHLBI Exome Sequencing Project (http://evs.gs.washington. edu/EVS/). This variant was also identified in one individual with DCM who had t wo other variants, including a TTN variant inherited in cis with this variant. F amily studies suggest that the TTN variants may be less likely disease causing b ut computational analyses (biochemical amino acid properties, conservation, Alig nGVGD, PolyPhen2, and SIFT) suggest that the Arg19067Cys variant may impact the protein (please note: the accuracy of these tools is unknown and this informatio n is not predictive enough to determine pathogenicity). Additional information i s needed to fully assess the clinical significance of the Arg19067Cys variant.
GeneDx RCV001356315 SCV000725317 likely benign not provided 2019-04-25 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 24503780)
Baylor Genetics RCV001336915 SCV001530436 uncertain significance Myopathy, myofibrillar, 9, with early respiratory failure 2018-01-24 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356315 SCV001551449 uncertain significance not provided no assertion criteria provided clinical testing The TTN p.Arg19994Cys variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs201614524) and ClinVar (classified as likely benign by GeneDx and uncertain significance by Laboratory for Molecular Medicine). The variant was identified in control databases in 17 of 279872 chromosomes (1 homozygous) at a frequency of 0.00006074 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: East Asian in 5 of 19474 chromosomes (freq: 0.000257), European (non-Finnish) in 10 of 127774 chromosomes (freq: 0.000078), African in 1 of 24194 chromosomes (freq: 0.000041) and Latino in 1 of 35352 chromosomes (freq: 0.000028), but was not observed in the Ashkenazi Jewish, European (Finnish), Other, or South Asian populations. The p.Arg19994 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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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