ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.97055G>A (p.Arg32352His)

gnomAD frequency: 0.00016  dbSNP: rs575939045
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000723859 SCV000203671 uncertain significance not provided 2018-02-12 criteria provided, single submitter clinical testing
Invitae RCV000460324 SCV000542480 uncertain significance Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2016-12-12 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000154035 SCV000616192 uncertain significance not specified 2016-11-11 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000723859 SCV000884800 uncertain significance not provided 2018-05-14 criteria provided, single submitter clinical testing The TTN: c.89351G>A; p.Arg29784His,variant is rare in the general population (<1% allele frequency in the Genome Aggregation Database) and have 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. While the clinical significance of such variants is considered uncertain, evidence suggests that the vast majority of missense variants do not contribute to the clinical outcome of DCM (Begay 2015). Given the available evidence, the clinical significance of the p.Arg13618Leu and p.Ala7671Gly variants cannot be determined with certainty.
GeneDx RCV000723859 SCV001794852 likely benign not provided 2021-04-08 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 25363768, 27956632)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000154035 SCV002104067 uncertain significance not specified 2022-02-28 criteria provided, single submitter clinical testing Variant summary: TTN c.89351G>A (p.Arg29784His) results in a non-conservative amino acid change located in the A-band region of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-05 in 248138 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in TTN causing Dilated Cardiomyopathy (6.4e-05 vs 0.00039), allowing no conclusion about variant significance. c.89351G>A has been reported in the literature in individuals affected with autistic spectrum disorder and hypertrophic cardiomyopathy (Iossifov_2014, Mademont-Soler_2017, Turner_2019). These reports do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. A co-occurrence with a pathogenic variant has been reported (MYBPC3 c.1624G>C, p.E542Q; Internal testing), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter (evaluation after 2014) cites the variant as likely benign and four ClinVar submitters (evaluation after 2014) cite it as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics RCV002372006 SCV002668016 uncertain significance Cardiovascular phenotype 2018-06-01 criteria provided, single submitter clinical testing The p.R23287H variant (also known as c.69860G>A), located in coding exon 175 of the TTN gene, results from a G to A substitution at nucleotide position 69860. The arginine at codon 23287 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity RCV000723859 SCV003822983 uncertain significance not provided 2019-03-12 criteria provided, single submitter clinical testing

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