ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.56255C>T (p.Pro18752Leu)

gnomAD frequency: 0.00015  dbSNP: rs200132226
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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 RCV000172306 SCV000054982 uncertain significance not provided 2013-06-24 criteria provided, single submitter research
Ambry Genetics RCV000246388 SCV000319631 uncertain significance Cardiovascular phenotype 2018-03-28 criteria provided, single submitter clinical testing The p.P9687L variant (also known as c.29060C>T), located in coding exon 116 of the TTN gene, results from a C to T substitution at nucleotide position 29060. The proline at codon 9687 is replaced by leucine, an amino acid with similar properties. This alteration has been reported as p.P16184L (c.48551C>T) as a secondary cardiac variant in an exome cohort using the NM_133378.4 isoform (Ng D et al. Circ Cardiovasc Genet. 2013;6(4):337-46). This alteration was also reported in a subject with dilated cardiomyopathy (DCM) who also had variants in other cardiac-related genes (Forleo C et al. PLoS ONE, 2017 Jul;12:e0181842). This amino acid position is not well 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 variant remains unclear.
Genetic Services Laboratory, University of Chicago RCV000500554 SCV000597693 uncertain significance not specified 2016-03-04 criteria provided, single submitter clinical testing
Invitae RCV000643101 SCV000764788 uncertain significance Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2018-01-02 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000172306 SCV000844720 uncertain significance not provided 2017-08-28 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000764325 SCV000895344 uncertain significance Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J; Tibial muscular dystrophy; Myopathy, myofibrillar, 9, with early respiratory failure; Early-onset myopathy with fatal cardiomyopathy; Hypertrophic cardiomyopathy 9 2018-10-31 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000172306 SCV001152863 uncertain significance not provided 2024-02-01 criteria provided, single submitter clinical testing
GeneDx RCV000172306 SCV001801756 likely benign not provided 2022-05-10 criteria provided, single submitter clinical testing See Variant Classification Assertion Criteria.
Revvity Omics, Revvity RCV000172306 SCV003822341 uncertain significance not provided 2021-10-27 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000500554 SCV004020328 uncertain significance not specified 2023-06-26 criteria provided, single submitter clinical testing Variant summary: TTN c.48551C>T (p.Pro16184Leu) results in a non-conservative amino acid change located in the A-band of the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00017 in 247942 control chromosomes (gnomAD). c.48551C>T has been reported in the literature in individuals affected with dilated cardiomyopathy or sudden unexplained death without strong evidence of causality (Mates_2018, Campuzano_2015, Forleo_2017). These reports do not provide unequivocal conclusions about association of the variant with Limb-Girdle Muscular Dystrophy, Type 2J. The following publications have been ascertained in the context of this evaluation (PMID: 29511324, 26516846, 28750076). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=6) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Mayo Clinic Laboratories, Mayo Clinic RCV000172306 SCV004225855 uncertain significance not provided 2022-06-21 criteria provided, single submitter clinical testing BP4

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