ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.56947G>A (p.Ala18983Thr)

gnomAD frequency: 0.00007  dbSNP: rs377000174
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Total submissions: 10
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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 RCV000213289 SCV000272694 likely benign not specified 2018-11-09 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx RCV000726732 SCV000617124 likely benign not provided 2020-12-15 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 22526018, 23446887, 31983221)
Invitae RCV000548016 SCV000643404 uncertain significance Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2017-06-26 criteria provided, single submitter clinical testing
Eurofins Ntd Llc (ga) RCV000726732 SCV000702564 uncertain significance not provided 2016-10-14 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV000768979 SCV000900352 uncertain significance Cardiomyopathy 2021-11-04 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000213289 SCV001821373 uncertain significance not specified 2021-08-23 criteria provided, single submitter clinical testing Variant summary: TTN c.49243G>A (p.Ala16415Thr) results in a non-conservative amino acid change located in the A-band domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.6e-05 in 249438 control chromosomes (gnomAD and publication data). This frequency is not significantly higher than expected for a pathogenic variant in TTN causing Dilated Cardiomyopathy (9.6e-05 vs 0.00039), allowing no conclusion about variant significance. c.49243G>A has been reported in the literature in individuals affected with Dilated cardiomyopathy, Hypertrophic cardiomyopathy and Muscular dystrophy as well as in one healthy control (Vasli_2012, Lopes_2013, 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 ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=4) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics RCV002433937 SCV002746203 uncertain significance Cardiovascular phenotype 2018-07-05 criteria provided, single submitter clinical testing The p.A9918T variant (also known as c.29752G>A), located in coding exon 118 of the TTN gene, results from a G to A substitution at nucleotide position 29752. The alanine at codon 9918 is replaced by threonine, an amino acid with similar properties. This variant (reported as p.A16415T) was detected in the compound heterozygous state with TTN p.V998M (reported as p.V1034M) in a patient with limb girdle muscular dystrophy and her affected brother (Vasli N et al. Acta Neuropathol. 2012;124:273-83). This alteration was also identified in a hypertrophic cardiomyopathy cohort; however, clinical details were limited (Lopes LR et al. J. Med. Genet. 2013;50:228-39). This amino acid position is highly conserved through mammals but not in all 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 Omics RCV000726732 SCV003821023 uncertain significance not provided 2022-12-21 criteria provided, single submitter clinical testing
Clinical Genetics, Academic Medical Center RCV000726732 SCV001925277 uncertain significance not provided no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000726732 SCV001963541 uncertain significance not provided no assertion criteria provided clinical testing

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