ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.86076dup (p.Ser28693fs) (rs1285329277)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000618269 SCV000736874 pathogenic Cardiovascular phenotype 2018-08-30 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense);Strong segregation with disease (lod >3 = >10 meioses)
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000623645 SCV000740482 pathogenic not provided 2017-01-30 criteria provided, single submitter clinical testing
GeneDx RCV000623645 SCV001167935 pathogenic not provided 2019-01-08 criteria provided, single submitter clinical testing The c.81153dupA pathogenic variant in the TTN gene has been previously reported in association with DCM and has also been described as c.58880insA and c.86078insA, due to the use of alternate transcripts and nomenclature (Yoskovitz et al., 2012; Franaszczyk et al., 2017). Yoskovitz et al. (2012) identified this variant in a large Arabian family with familial DCM, and showed that this variant segregated with disease in 12 affected relatives in addition to the proband. Additionally, this variant was reported in two Caucasian brothers with DCM who both also harbored a missense variant in the MYH6 gene (Franaszczyk et al., 2017). The c.81153dupA variant has not been observed at a significant frequency in large population cohorts (Lek et al., 2016). The c.81153dupA variant causes a shift in reading frame starting at codon serine 27052, changing it to an isoleucine, and creating a premature stop codon at position 2 of the new reading frame, denoted p.Ser27052IlefsX2. This pathogenic variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other truncating TTN variants have been reported in approximately 3% of control alleles (Herman et al., 2012). However, c.81153dupA is located in the A-band region of titin, where the majority of truncating pathogenic variants associated with DCM have been reported (Herman et al., 2012). Moreover, a functional study using induced pluriopotent stem cell-derived cardiomyocytes generated from the proband described by Yoskovitz et al. (2012) demonstrated abnormal contraction and calcium handling, defects in assembly and maintenance of stable sarcomeric structure, and altered response to positive inotropic interventions when compared to healthy cardiomyocytes (Schick et al., 2018).
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001170546 SCV001333132 pathogenic Cardiomyopathy 2018-03-16 criteria provided, single submitter clinical testing

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