ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.86821+2T>A (rs397517735)

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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 RCV000040727 SCV000064418 likely pathogenic Primary dilated cardiomyopathy 2019-01-18 criteria provided, single submitter clinical testing The c.79117+2T>A variant in TTN has been identified in 4 individuals with DCM and segregated with the disease in 5 affected relatives from 3 families (Norton 2013, Herman 2012, LMM data). It has also been identified 1/21992 African chromosomes by gnomAD (; however, the quality of this region was low. This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. Splice site variants and other truncating variants in TTN are strongly associated with DCM if they impact the exons encoding for the A-band (Herman 2012, Pugh 2014) and/or are located in an exon that is highly expressed in the heart (Roberts 2015). The c.79117+2T>A variant is located in A-band. Loss of function of the TTN gene is an established disease mechanism in autosomal dominant DCM. ACMG/AMP criteria applied: PVS1_Moderate, PS4_Moderate, PP1_Moderate.
GeneDx RCV000184278 SCV000236901 pathogenic not provided 2018-11-13 criteria provided, single submitter clinical testing The c.81898+2 T>A pathogenic variant in the TTN gene, also described as IVS275+2 T>A due to the use of an alternate transcript, has previously been described in multiple unrelated individuals with DCM and was reported to segregate with disease in two different families (Herman et al., 2012; Norton et al., 2013). This variant has also been identified in several unrelated individuals referred for cardiomyopathy genetic testing at GeneDx. Moreover, the c.81898+2 T>A is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The c.81898+2 T>A variant destroys the canonical splice donor site of intron 276 and is predicted to cause abnormal gene splicing. This variant is expected to lead to either an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Although other truncating TTN variants have been reported in approximately 3% of control alleles, the c.81898+2 T>A variant is located in the A band region of titin, where the majority of truncating variants associated with DCM have been reported (Herman et al., 2012). In summary, c.81898+2 T>A in the TTN gene is interpreted as a pathogenic variant
Invitae RCV000627778 SCV000286884 pathogenic Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2020-10-10 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 326 of the TTN gene. It is expected to disrupt mRNA splicing and likely results in an absent or disrupted protein product. This variant is found in the A-band of this gene. Truncating variants in the A-band of TTN are significantly overrepresented in patients with dilated cardiomyopathy and are considered to be likely pathogenic for the disease (PMID: 25589632). This particular variant has been reported to segregate with dilated cardiomyopathy (PMID: 22335739, 23418287). This variant is also known as IVS 275+2T>A and c.81898+2T>A in the literature. ClinVar contains an entry for this variant (Variation ID: 47458). For these reasons, this variant has been classified as Pathogenic.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000184278 SCV000708831 pathogenic not provided 2017-05-30 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000768876 SCV000900249 pathogenic Cardiomyopathy 2017-06-12 criteria provided, single submitter clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000040727 SCV000995191 pathogenic Primary dilated cardiomyopathy 2018-04-06 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000184278 SCV001714627 pathogenic not provided 2020-02-25 criteria provided, single submitter clinical testing PVS1, PM1, PP1

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