ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.30718G>T (p.Val10240Phe) (rs111671438)

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Total submissions: 18
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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 RCV000172682 SCV000051432 likely benign not provided 2013-06-24 criteria provided, single submitter research
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000040111 SCV000063802 uncertain significance not specified 2014-03-13 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The Val8996Phe vari ant in TTN has now been reported by our laboratory in two Caucasian adults with cardiomyopathy: one with family history of LVNC and sudden death, who carried a pathogenic variant in another gene, and one with family history of DCM and sudde n death. This variant has also been identified in 0.2% (14/7946) European Americ an chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.e du; dbSNP rs111671438). While this frequency suggests that this variant is more likely benign, it is too low to confidently rule out a disease causing role. Com putational prediction tools and conservation analyses do not provide strong supp ort for or against an impact to the protein. Additional information is needed to fully assess its clinical significance.
GeneDx RCV000040111 SCV000237060 likely benign not specified 2017-09-14 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.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000172682 SCV000333469 uncertain significance not provided 2015-07-30 criteria provided, single submitter clinical testing
Invitae RCV001084360 SCV000555391 likely benign Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2019-12-31 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000040111 SCV000597701 uncertain significance not specified 2016-08-09 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000040111 SCV000616052 likely benign not specified 2016-12-02 criteria provided, single submitter clinical testing
Phosphorus, Inc. RCV000578117 SCV000679957 uncertain significance Dilated cardiomyopathy 1G 2017-08-01 criteria provided, single submitter clinical testing
Phosphorus, Inc. RCV000577956 SCV000679958 uncertain significance Limb-girdle muscular dystrophy, type 2J 2017-08-01 criteria provided, single submitter clinical testing
Phosphorus, Inc. RCV000578036 SCV000679959 uncertain significance Tibial muscular dystrophy 2017-08-01 criteria provided, single submitter clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000852879 SCV000995613 likely benign Cardiomyopathy; Long QT syndrome; Hypertrophic cardiomyopathy 2018-04-23 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000172682 SCV001153002 uncertain significance not provided 2019-09-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000578036 SCV001288946 benign Tibial muscular dystrophy 2018-01-12 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 Clinical Services Laboratory,Illumina RCV000578117 SCV001288947 uncertain significance Dilated cardiomyopathy 1G 2018-01-12 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 Clinical Services Laboratory,Illumina RCV001129423 SCV001288948 benign Myopathy, myofibrillar, 9, with early respiratory failure 2018-01-12 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 Clinical Services Laboratory,Illumina RCV000577956 SCV001288949 uncertain significance Limb-girdle muscular dystrophy, type 2J 2018-01-12 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 Clinical Services Laboratory,Illumina RCV001129424 SCV001288950 uncertain significance Myopathy, early-onset, with fatal cardiomyopathy 2018-01-12 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.
Integrated Genetics/Laboratory Corporation of America RCV000040111 SCV001360730 likely benign not specified 2019-12-24 criteria provided, single submitter clinical testing Variant summary: TTN c.26986G>T (p.Val8996Phe) results in a non-conservative amino acid change located in the I-band region of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00084 in 151082 control chromosomes, predominantly at a frequency of 0.0018 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2.9-fold the estimated maximal allele frequency expected for a pathogenic variant in TTN causing Cardiomyopathy phenotype (0.00063), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.26986G>T in individuals affected with Cardiomyopathy and no experimental evidence demonstrating an impact on protein function have been reported in the literature. Co-occurrence with another pathogenic variant has been reported (MYH7 c.1207C>T, p.Arg403Trp-internal sample), providing supporting evidence for a benign role. Seven ClinVar submitters (evaluation after 2014) have cited the variant as likely benign (n=4) and uncertain significance (n=3). Based on the evidence outlined above, the variant was classified as likely benign.

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