ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.18776C>G (p.Thr6259Ser)

gnomAD frequency: 0.00262  dbSNP: rs72648949
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Total submissions: 24
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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 RCV000039914 SCV000051716 benign not specified 2013-06-24 criteria provided, single submitter research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000039914 SCV000063605 likely benign not specified 2015-04-09 criteria provided, single submitter clinical testing p.Thr5015Ser in exon 61 of TTN: This variant is not expected to have clinical si gnificance because it has been identified in 0.5% (318/66490) of European chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs72648949).
GeneDx RCV000039914 SCV000238258 benign not specified 2017-01-24 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.
Genetic Services Laboratory, University of Chicago RCV000039914 SCV000249237 likely benign not specified 2014-10-31 criteria provided, single submitter clinical testing
Invitae RCV001080584 SCV000286476 benign Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2024-01-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000246252 SCV000318128 benign Cardiovascular phenotype 2020-05-12 criteria provided, single submitter clinical testing This alteration is classified as 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.
Eurofins Ntd Llc (ga) RCV000039914 SCV000332588 likely benign not specified 2015-07-09 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000289663 SCV000424503 benign Myopathy, myofibrillar, 9, with early respiratory failure 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina RCV000341928 SCV000424504 benign Tibial muscular dystrophy 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina RCV000380242 SCV000424505 uncertain significance Early-onset myopathy with fatal cardiomyopathy 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina RCV000283432 SCV000424506 uncertain significance Autosomal recessive limb-girdle muscular dystrophy type 2J 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina RCV000340760 SCV000424507 uncertain significance Dilated cardiomyopathy 1G 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego RCV000852902 SCV000995641 benign Primary dilated cardiomyopathy; Arrhythmogenic right ventricular cardiomyopathy; Atrial fibrillation 2019-06-11 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000229581 SCV001153064 likely benign not provided 2023-11-01 criteria provided, single submitter clinical testing TTN: BP4, BS2
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV001170640 SCV001333232 benign Cardiomyopathy 2017-11-21 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000039914 SCV001361689 benign not specified 2019-08-19 criteria provided, single submitter clinical testing Variant summary: TTN c.15044C>G (p.Thr5015Ser) results in a conservative amino acid change located in the I-band region of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0032 in 247936 control chromosomes in the gnomAD database, including 3 homozygotes. The observed variant frequency is approximately 5.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Cardiomyopathy phenotype (0.00063), strongly suggesting that the variant is benign. c.15044C>G has been reported in the literature in individuals affected with Cardiomyopathy (example Pugh_2014). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. At-least one co-occurrence with another likely pathogenic variant has been reported in an individual with a clinical diagnosis and family history of DCM ( TTN c.50143+1G>A, Pugh_2014), providing supporting evidence for a benign role. 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 (benign=2, likely benign = 2, VUS = 1). Based on the evidence outlined above, the variant was classified as benign.
Athena Diagnostics Inc RCV000039914 SCV001880224 benign not specified 2020-12-03 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000229581 SCV002048438 benign not provided 2023-09-21 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000229581 SCV001741348 likely benign not provided no assertion criteria provided clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000229581 SCV001799561 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics, Academic Medical Center RCV000039914 SCV001922000 benign not specified no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000039914 SCV001929935 benign not specified no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000039914 SCV001956289 benign not specified no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000229581 SCV001974587 likely benign not provided no assertion criteria provided clinical testing

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