ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.51809G>T (p.Ser17270Ile) (rs200650668)

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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000040327 SCV000064018 likely benign not specified 2014-05-01 criteria provided, single submitter clinical testing Ser14702Ile in exon 222 of TTN: This variant is not expected to have clinical si gnificance due to a lack of conservation across species, including mammals. Of n ote, multiple mammals have an isoleucine (Ile) at this position despite high nea rby amino acid conservation. In addition, computational prediction tools do not suggest a high likelihood of impact to the protein. It has been identified in 7/ 8240 European American chromosomes by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS/; dbSNP rs200650668).
GeneDx RCV000725456 SCV000237274 likely benign not provided 2020-10-16 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 28045975)
Invitae RCV000227290 SCV000286707 uncertain significance Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2017-12-21 criteria provided, single submitter clinical testing
Ambry Genetics RCV000250975 SCV000317531 likely benign Cardiovascular phenotype 2020-01-30 criteria provided, single submitter clinical testing In silico models in agreement (benign);Subpopulation frequency in support of benign classification
Illumina Clinical Services Laboratory,Illumina RCV000374388 SCV000422942 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 RCV000279940 SCV000422943 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 RCV000334677 SCV000422944 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 RCV000389173 SCV000422945 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 RCV000294783 SCV000422946 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000725456 SCV000700974 uncertain significance not provided 2018-06-01 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000725456 SCV001152885 uncertain significance not provided 2021-04-01 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001170610 SCV001333199 likely benign Cardiomyopathy 2017-11-15 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001285234 SCV001471635 uncertain significance none provided 2019-08-19 criteria provided, single submitter clinical testing The TTN c.51809G>T; p.Ser17270Ile variant (rs200650668; ClinVar Variation ID: 47057) 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.Ser17270Ile 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000040327 SCV001737715 benign not specified 2021-06-01 criteria provided, single submitter clinical testing Variant summary: TTN c.44105G>T (p.Ser14702Ile) results in a non-conservative amino acid change located in the A-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 0.00042 in 247482 control chromosomes, including one homozygote (gnomAD). The variant was observed predominantly within the Non-Finnish European subpopulation at a frequency of 0.00086. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy phenotype (0.00039), strongly suggesting that the variant is a benign polymorphism. c.44105G>T has been reported in the literature in an individual affected with Dilated Cardiomyopathy (Franaszczyk_2017), however it was also reported in two individuals without a cardiac phenotype (Khan_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments, i.e. 5 calling it a VUS, while 3 classifying it as likely benign. Based on the evidence outlined above, the variant was classified as benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000725456 SCV001740726 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics,Academic Medical Center RCV000725456 SCV001923204 likely benign not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000725456 SCV001932297 likely benign not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000040327 SCV001956075 benign not specified no assertion criteria provided clinical testing

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