ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.80425G>A (p.Gly26809Ser) (rs369941201)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000154047 SCV000051304 uncertain significance not provided 2013-06-24 criteria provided, single submitter research
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000040656 SCV000064347 likely benign not specified 2020-12-21 criteria provided, single submitter clinical testing The p.Gly24241Ser variant in TTN is classified as likely benign because it has been identified in 0.05% (62/127490) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Additionally, this variant has been identified in at least 2 individuals that harbored other disease-causing variants in the same gene or other cardiomyopathy associated genes (LMM data) . ACMG/AMP Criteria applied: BS1, BP5.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000154047 SCV000203685 uncertain significance not provided 2017-04-03 criteria provided, single submitter clinical testing
GeneDx RCV000040656 SCV000237599 uncertain significance not specified 2017-09-07 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the A-band of TTN gene. The G25168S variant has been reported in a 15-year-old male with infantile onset left ventricular enlargement/dilation (using transcript NM_133378.4 and denoted c.72721 A>G; p.Gly24241Ser); however, this individual harbored several other variants including a different TTN variant classified as likely pathogenic (Pugh et al., 2014). In addition, although this variant has been identified in multiple unrelated probands referred to GeneDx for cardiomyopathy testing, the majority of these individuals were found to harbor co-occurring variants. The G25168S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Furthermore, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Nonetheless, while this missense variant is located in the A-band region of TTN, the majority of pathogenic variants in the TTN gene associated with DCM are truncating variants within this region (Herman et al., 2012). Finally, this variant is observed in 61/125,688 (0.05%) European (non-Finnish) alleles in large population cohorts (Lek et al., 2016). Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Ambry Genetics RCV000242849 SCV000320632 likely benign Cardiovascular phenotype 2020-04-06 criteria provided, single submitter clinical testing In silico models in agreement (benign);Subpopulation frequency in support of benign classification
Invitae RCV000471525 SCV000542713 uncertain significance Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2017-10-27 criteria provided, single submitter clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000852499 SCV000995195 uncertain significance Cardiomyopathy 2019-03-15 criteria provided, single submitter clinical testing

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