ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.104261C>T (p.Ala34754Val) (rs727505020)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000156444 SCV000206163 uncertain significance not specified 2014-05-01 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The Ala32186Val (96 557C>T) variant in TTN has not been previously reported in individuals with card iomyopathy or in large population studies. Computational prediction tools and co nservation analysis are limited for this variant and the amino acid is poorly co nserved across species. Additional information is needed to fully assess the cl inical significance of the variant.
Invitae RCV000475607 SCV000542797 uncertain significance Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2016-12-25 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 34754 of the TTN protein (p.Ala34754Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs727505020, ExAC 0.02%) but has not been reported in the literature in individuals with a TTN-related disease. ClinVar contains an entry for this variant (Variation ID: 179648). Algorithms developed to predict the effect of missense changes on protein structure and function are unavailable for the TTN gene. In summary, this variant is a rare missense change with unknown impact on protein function. Missense variants in this region of the TTN gene are typically not causative for cardiac disease, but may be relevant for neuromuscular disorders. However, the available evidence is currently insufficient to determine this variant's role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000156444 SCV000730443 likely benign not specified 2017-10-27 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics RCV000620906 SCV000735267 likely benign Cardiovascular phenotype 2020-03-26 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other strong data supporting benign classification
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000156444 SCV001160289 uncertain significance not specified 2019-03-01 criteria provided, single submitter clinical testing The TTN c.96557C>T; p.Ala32186Val variant (rs727505020; ClinVar Variation ID: 179648) 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.Ala32186Val variant cannot be determined with certainty.
Institute of Human Genetics, University of Leipzig Medical Center RCV001262303 SCV001440117 uncertain significance Familial hypertrophic cardiomyopathy 9 2019-01-01 criteria provided, single submitter clinical testing

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