ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.98726T>C (p.Val32909Ala) (rs368877793)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000040877 SCV000064568 uncertain significance not specified 2011-10-11 criteria provided, single submitter clinical testing The Val30341Ala variant has not been reported in the literature or previously id entified by our laboratory. Valine (Val) at position 30341 is conserved in mamma ls, chicken, and fish, though frog carries an isoleucine (Ile), raising the poss ibility that a change may be tolerated. Computational tools (AlignGVGD and SIFT) predict this variant to be benign, though their accuracy is unknown. At this ti me, additional data is required to assess the clinical significance of this vari ant.
GeneDx RCV000725120 SCV000237857 uncertain significance not provided 2017-04-03 criteria provided, single submitter clinical testing The V31268A variant of uncertain significance in the TTN gene has been reported in a 3-month-old female with a clinical diagnosis of DCM who also harbored another variant of uncertain significance in the TTN gene (Pugh et al., 2014). Additionally, two other clinical laboratories classify V31268A as a variant of uncertain signififance (SCV000064568.4, SCV000334249.2; Landrum et al., 2016). The V31268A variant has been observed in approximately 0.03% of alleles from individuals of European in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The V31268A variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Although this substitution occurs at a position where amino acids with similar properties to valine are tolerated across species, alanine is not tolerate at this position. Furthermore, in silico analysis predicts this variant is probably damaging to the protein structure/function.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000725120 SCV000334249 uncertain significance not provided 2018-08-23 criteria provided, single submitter clinical testing
Invitae RCV000525675 SCV000643995 uncertain significance Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2017-12-12 criteria provided, single submitter clinical testing
Ambry Genetics RCV000622118 SCV000735929 likely benign Cardiovascular phenotype 2020-02-12 criteria provided, single submitter clinical testing In silico models in agreement (benign);Insufficient evidence;Other strong data supporting benign classification
CeGaT Praxis fuer Humangenetik Tuebingen RCV000725120 SCV001152615 uncertain significance not provided 2019-01-01 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001170525 SCV001333108 likely benign Cardiomyopathy 2018-05-31 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001287431 SCV001474123 uncertain significance none provided 2019-09-30 criteria provided, single submitter clinical testing The TTN c.98726T>C; p.Val32909Ala variant (rs368877793; ClinVar Variation ID: 47608) is rare in the general population (<1% allele frequency in the Genome Aggregation Database) and has not been reported in the medical literature in association with dilated cardiomyopathy (DCM) or other TTN-related disease. The clinical relevance of rare missense variants in this gene, which are identified on average once per individual sequenced in affected populations (Herman 2012), is not well understood. Yet, evidence suggests that the vast majority of such missense variants do not contribute to the clinical outcome of DCM (Begay 2015). Thus, the clinical significance of the p.Val32909Ala variant cannot be determined with certainty. References: Begay RL et al. Role of Titin Missense Variants in Dilated Cardiomyopathy. J Am Heart Assoc. 2015 Nov 13;4(11). Herman DS et al. Truncations of titin causing dilated cardiomyopathy. N Engl J Med. 2012 Feb 16;366(7):619-28.

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