ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.105719G>A (p.Arg35240Gln)

gnomAD frequency: 0.00004  dbSNP: rs530537991
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Mass General Brigham Personalized Medicine RCV000155663 SCV000205372 likely benign not specified 2015-04-04 criteria provided, single submitter clinical testing p.Arg32672Gln in exon 307 of TTN: This variant is not expected to have clinical significance due to a lack of conservation across species, including mammals. Of note, 5 mammals (gibbon, bat, microbat, big brown bat, and platypus) have a glu tamine (Gln) at this position despite high nearby amino acid conservation. This variant has been identified in 4/8620 East Asian chromosomes by the Exome Aggreg ation Consortium (ExAC,; dbSNP rs530537991).
Invitae RCV000457467 SCV000542674 uncertain significance Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2016-12-25 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 35240 of the TTN protein (p.Arg35240Gln). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs530537991, ExAC 0.05%) but has not been reported in the literature in individuals with a TTN-related disease. ClinVar contains an entry for this variant (Variation ID: 178891). Algorithms developed to predict the effect of missense changes on protein structure and function are unavailable for the TTN gene. The glutamine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. 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 RCV001529846 SCV000730446 likely benign not provided 2020-11-04 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 23396983)
Ambry Genetics RCV000617881 SCV000735277 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 RCV000155663 SCV001158189 uncertain significance not specified 2019-03-01 criteria provided, single submitter clinical testing The c.98015G>A; p.Arg32672Gln variant (rs530537991) has not been reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the Genome Aggregation Database (gnomAD) with an overall population frequency of 0.006 percent (identified on 18 out of 280,138 chromosomes) and has been reported to the ClinVar database (Variation ID: 178891). This is a missense variant in a weakly conserved nucleotide, but computational analyses (Alamut v.2.11) predict that this variant may impact splicing by creating a novel cryptic donor splice site/weakening the nearby canonical splice site. Altogether, there is not enough evidence to classify the p.Arg32672Gln variant with certainty.

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