ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.107889del (p.Lys35963fs) (rs281864930)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000184369 SCV000229485 pathogenic not provided 2018-08-14 criteria provided, single submitter clinical testing
GeneDx RCV000184369 SCV000236994 pathogenic not provided 2018-08-22 criteria provided, single submitter clinical testing The c.102966delA pathogenic variant in the M-band region of the TTN gene (also referred to as c.100185delA, c.107889delA, and g.293376delA, due to alternate transcript nomenclature) has been previously reported in multiple individuals with TTN-related disorders who were either homozygous, compound heterozgyous with a second variant on the opposite TTN allele (in trans), or heterozygous for this variant (Hackman et al., 2008; Ceyhan-Birsoy et al., 2013; Evila et al., 2014; Evila et al., 2016). This variant (reported as c.100185delA) was identified in the compound heterozygous state with a pathogenic nonsense variant in an individual with suspected muscular dystrophy who was noted to have moderately elevated serum creatine phosphokinase levels and findings on muscle biopsy consistent with centronuclear myopathy (Ceyhan-Birsoy et al., 2013). The c.102966delA variant (reported as c.107889delA) was also identified in two patients with severe tibial muscular dystrophy (TMD), one patient was homozygous for this variant while the other patient harbored a second TTN frameshift variant in trans; the heterozygous parents of these individuals were asymptomatic (Evila et al., 2014). Two patients with distal titinopathy also harbored this variant, one patient harbored an additional frameshift TTN variant while the other patient had no second variant identified (Evila et al., 2016). This variant has also been reported (as g.293378delA) in the heterozygous state in individuals from two Spanish families with tibial muscular dystrophy (TMD) (Hackman et al., 2008).Considering cardiac phenotypes, Campuzano et al. (2015) identified this variant (reported as c.100185delA) in both dilated cardiomyopathy (DCM) and sudden unexplained death patient cohorts, but specific clinical details and segregation data were not provided. The c.102966delA variant has been identified in conjunction with a second likely pathogenic or pathogenic TTN variant in other unrelated individuals referred for genetic testing for neuromuscular disorders at GeneDx. This variant causes a shift in reading frame starting at codon lysine 34322, changing it to an asparagine, and creating a premature stop codon at position 9 of the new reading frame, denoted p.Lys34322AsnfsX9. The c.102966delA variant is predicted to cause loss of normal protein function through protein truncation, as the last 29 amino acids of the titin protein are lost and replaced with 8 incorrect amino acids. Finally, this variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016).In summary, c.102966delA in the TTN gene is interpreted as a pathogenic variant.
GeneReviews RCV000031995 SCV000054699 pathologic Distal myopathy Markesbery-Griggs type 2012-08-23 no assertion criteria provided curation Converted during submission to Pathogenic.
GenomeConnect, ClinGen RCV000844994 SCV000986824 not provided Hereditary myopathy with early respiratory failure no assertion provided phenotyping only Variant interpretted as pathogenic and reported on 01/12/2018 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.