ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.12587C>A (p.Ser4196Ter) (rs370912401)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000041096 SCV000064787 uncertain significance not specified 2012-05-23 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The Ser3958X va riant in TTN has been identified in 1/6588 European American chromosomes from a broad population by the NHLBI Exome Sequencing Project ( .edu/EVS). This frequency is not high enough to rule out a disease causing role as this individual could have been presymptomatic. This nonsense variant leads t o a premature termination codon at position 3958, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the TTN gene is strongly associated with DCM (Herman 2012). Although this data supports that the Ser3958X variant may be pathogenic, this variant has not been detected in isola tion and thus, additional studies are needed to fully assess its clinical signif icance.
Invitae RCV000233246 SCV000286437 uncertain significance Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2016-03-24 criteria provided, single submitter clinical testing
GeneDx RCV000766916 SCV000680711 likely pathogenic not provided 2018-08-10 criteria provided, single submitter clinical testing The S3879X likely pathogenic variant in the TTN gene, also known as S4196X due to use of alternate nomenclature, has been reported previously in association with DCM (Pugh et al., 2014; Walsh et al., 2017); however, specific clinical details were not provided. The S3879X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). S3879X is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Truncating TTN variants have been reported in approximately 3% of control alleles, and the majority of truncating pathogenic variants associated with DCM have been reported in the A-band (Herman et al., 2012). However, the S3879X variant is located in one of the constitutive exons in the I-band region, and recent studies suggest that truncating variants affecting constitutive exons throughout the TTN gene are also significantly associated with DCM (Deo, 2016; Schafer et al., 2017).

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