ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.69338G>A (p.Arg23113Gln) (rs370890454)

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Total submissions: 8
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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 RCV000172270 SCV000054949 uncertain significance not provided 2013-06-24 criteria provided, single submitter research
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000219897 SCV000272739 uncertain significance not specified 2015-06-30 criteria provided, single submitter clinical testing The p.Arg20545Gln variant in TTN has not been previously reported in individuals with cardiomyopathy, but has been identified in 6/66666 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP r s370890454). Computational prediction tools and conservation analysis suggest th at the p.Arg20545Gln variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical signi ficance of the p.Arg20545Gln variant is uncertain.
Ambry Genetics RCV000247024 SCV000318967 uncertain significance Cardiovascular phenotype 2013-10-25 criteria provided, single submitter clinical testing The p.R20545Q variant (also known as c.61634G>A) is located in coding exon 272 of the TTN gene. This alteration results from a G to A substitution at nucleotide position 61634. The arginine at codon 20545 is replaced by glutamine, an amino acid with highly similar properties. This variant was observed in a 4-year old male diagnosed with methylmalonic acidemia and hyperhomocysteinemia in transwith another variant. The variant was found in whole exome analysis. This child did not show any symptoms of cardiomyopathy, but given the young age this diagnosis cannot be ruled out (Yu et al.Am. J. Hum. Genet. 2013 Sep;93(3):506-14).Based on data from the NHLBI Exome Sequencing Project (ESP), the A-allele has an overall frequency of approximately 0.01% (1/12050). This variant was not observed in 3824 of African American alleles, but observed in 0.01% (1/8226) of European American alleles studied. This variant was not reported in population-based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP) and 1000 Genomes Project. This amino acid position is highly conserved on sequence alignment. This variant is predicted to be probably damaging by PolyPhen in silico analyses. Since supporting evidence is limited at this time, the clinical significance of p.R20545Q remains unclear.
Invitae RCV000470047 SCV000542464 uncertain significance Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2017-10-10 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000219897 SCV000616129 uncertain significance not specified 2017-07-21 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769962 SCV000901388 uncertain significance Cardiomyopathy 2016-06-06 criteria provided, single submitter clinical testing
GeneDx RCV000172270 SCV000982836 likely benign not provided 2018-06-05 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000219897 SCV001519613 uncertain significance not specified 2021-03-11 criteria provided, single submitter clinical testing Variant summary: TTN c.61634G>A (p.Arg20545Gln) results in a conservative amino acid change located in the A- band region (cardiodb.org) 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 9.3e-05 in 248036 control chromosomes, predominantly at a frequency of 0.0002 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in TTN causing Dilated Cardiomyopathy (0.0002 vs 0.00039), allowing no conclusion about variant significance. c.61634G>A has been reported in the literature in individuals affected with Dilated Cardiomyopathy (e.g. Haas_2015, Mazzarotto_2020). These reports 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. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, citing the variant as likely benign (n=1) and uncertain significance (n=4). Based on the evidence outlined above, the variant was classified as uncertain significance.

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