ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.9488G>A (p.Arg3163His)

gnomAD frequency: 0.00036  dbSNP: rs149755500
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Total submissions: 11
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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 RCV000172724 SCV000051337 likely benign not provided 2013-06-24 criteria provided, single submitter research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000152483 SCV000201615 uncertain significance not specified 2015-05-26 criteria provided, single submitter clinical testing The p.Arg3163His variant in TTN has been previously identified by our laboratory in 1 unaffected individual with a family history of DCM, hypertrophy with fibro sis, and SCD. It has also been identified in 19/66478 European chromosomes by th e Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs14 9755500). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive e nough to determine pathogenicity. In summary, the clinical significance of the p.Arg3163His variant is uncertain.
GeneDx RCV000172724 SCV000238062 likely benign not provided 2021-01-21 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 23861362, 25790293, 30415094)
Invitae RCV000460977 SCV000542703 uncertain significance Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2016-09-15 criteria provided, single submitter clinical testing
Eurofins Ntd Llc (ga) RCV000172724 SCV000701245 uncertain significance not provided 2017-01-11 criteria provided, single submitter clinical testing
Ambry Genetics RCV000617183 SCV000735600 likely benign Cardiovascular phenotype 2019-08-19 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV001171057 SCV001333726 likely benign Cardiomyopathy 2019-04-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000152483 SCV002766513 uncertain significance not specified 2022-11-14 criteria provided, single submitter clinical testing Variant summary: TTN c.9488G>A (p.Arg3163His) results in a non-conservative amino acid change located in the I-band region of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 250452 control chromosomes. This frequency is not higher than expected for a pathogenic variant in TTN causing Dilated Cardiomyopathy (0.00018 vs 0.00039), allowing no conclusion about variant significance. c.9488G>A has been reported in the literature in a sudden unexpected death case (Scheiper_2018), in a family with muscular dystrophy (Dardas_2020), and in a cohort of individuals not selected for arrhythmia, cardiomyopathy, or a family history of sudden death (Ng_2013). These report(s) do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite this variant as likely benign (n = 3) or uncertain significance (n = 3). Based on the evidence outlined above, the variant was classified as uncertain significance.
Revvity Omics, Revvity Omics RCV000172724 SCV003819770 uncertain significance not provided 2023-10-04 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000172724 SCV004225923 uncertain significance not provided 2023-06-21 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000172724 SCV004562229 uncertain significance not provided 2023-09-28 criteria provided, single submitter clinical testing The TTN c.9488G>A; p.Arg3163His variant (rs149755500; ClinVar Variation ID: 166298) is rare in the general population (<0.2% 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.Arg3163His variant cannot be determined with certainty.

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