ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.53096G>A (p.Arg17699His) (rs72646808)

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Total submissions: 15
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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 RCV000172663 SCV000051448 likely benign not provided 2013-06-24 criteria provided, single submitter research
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000040340 SCV000064031 benign not specified 2017-10-26 criteria provided, single submitter clinical testing p.Arg15131His in Exon 226 of TTN: This variant is not expected to have clinical significance because it has been identified in 0.3% (354/125276) of European chr omosomes including 1 homozygote by the Genome Aggregation Database (gnomAD, http ://gnomad.broadinstitute.org; dbSNP rs72646808). BA1
GeneDx RCV000040340 SCV000237288 likely benign not specified 2017-09-11 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 RCV000040340 SCV000333251 likely benign not specified 2015-08-20 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000291245 SCV000422863 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 Clinical Services Laboratory,Illumina RCV000350259 SCV000422864 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.
Illumina Clinical Services Laboratory,Illumina RCV000404069 SCV000422865 uncertain significance Myopathy, early-onset, 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 Clinical Services Laboratory,Illumina RCV000315170 SCV000422866 uncertain significance 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 Clinical Services Laboratory,Illumina RCV000335069 SCV000422867 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.
Invitae RCV001086451 SCV000555148 likely benign Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2019-12-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000618788 SCV000736070 likely benign Cardiovascular phenotype 2018-11-21 criteria provided, single submitter clinical testing Subpopulation frequency in support of benign classification;Other data supporting benign classification
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770012 SCV000901438 likely benign Cardiomyopathy 2017-05-31 criteria provided, single submitter clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000852844 SCV000995575 benign Dilated cardiomyopathy 2019-05-08 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000172663 SCV001152877 uncertain significance not provided 2019-11-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000040340 SCV001159136 uncertain significance not specified 2019-05-10 criteria provided, single submitter clinical testing The TTN c.45392G>A; p.Arg15131His variant (rs72646808; ClinVar Variation ID: 47070) is rare in the general population (<1% allele frequency in the Genome Aggregation Database) and has not been reported in the medical literature in association with dilated cardiomyopathy (DCM) or other TTN-related disease. The clinical relevance of rare missense variants in this gene, which are identified on average once per individual sequenced in affected populations (Herman 2012), is not well understood. Yet, evidence suggests that the vast majority of such missense variants do not contribute to the clinical outcome of DCM (Begay 2015). Thus, the clinical significance of the p.Arg15131His variant cannot be determined with certainty. References: Begay RL et al. Role of Titin Missense Variants in Dilated Cardiomyopathy. J Am Heart Assoc. 2015 Nov 13;4(11). Herman DS et al. Truncations of titin causing dilated cardiomyopathy. N Engl J Med. 2012 Feb 16;366(7):619-28. Linke and Hamdani. Gigantic business: titin properties and function through thick and thin. Circ Res 2014; 114(6): 1052-1068.

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