ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.26494A>G (p.Ile8832Val)

gnomAD frequency: 0.00083  dbSNP: rs72648989
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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 RCV000172380 SCV000055043 uncertain significance not provided 2013-06-24 criteria provided, single submitter research
Laboratory for Molecular Medicine,Mass General Brigham Personalized Medicine RCV000154645 SCV000204320 uncertain significance not specified 2014-09-19 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The Ile7588Val vari ant in TTN has been identified by our laboratory in 1 Caucasian adult with HCM w ho also carried a pathogenic variant in another gene and 1 adult of unspecified ethnicity with DCM. This variant has been also been identified in 0.1% (8/8156) of European American chromosomes by the NHLBI Exome Sequencing Project (http://e vs.gs.washington.edu/EVS/, Ng 2013; dbSNP rs72648989). Computational prediction tools and conservation analysis suggest that the Ile7588Val variant may not impa ct the protein, though this information is not predictive enough to rule out pat hogenicity. In addition, 1 fish (yellowbelly pufferfish) carries a valine at thi s position, raising the possibility that this change may be tolerated. In summar y, while the clinical significance of the Ile7588Val variant is uncertain, its f requency in controls suggests that it is more likely to be benign.
GeneDx RCV000172380 SCV000238376 likely benign not provided 2020-09-23 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 23396983, 23861362)
Invitae RCV001083732 SCV000286537 likely benign Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2021-12-18 criteria provided, single submitter clinical testing
Eurofins NTD LLC (GA) RCV000172380 SCV000335896 uncertain significance not provided 2015-09-25 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000154645 SCV000597668 uncertain significance not specified 2016-09-20 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000172380 SCV000616038 likely benign not provided 2020-08-03 criteria provided, single submitter clinical testing
Illumina Laboratory Services,Illumina RCV001131542 SCV001291169 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 RCV001131543 SCV001291170 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 RCV001131544 SCV001291171 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 RCV001131545 SCV001291172 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 RCV001131546 SCV001291173 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.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001170862 SCV001333483 uncertain significance Cardiomyopathy 2017-12-20 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000154645 SCV001337972 likely benign not specified 2020-01-20 criteria provided, single submitter clinical testing Variant summary: TTN c.22762A>G (p.Ile7588Val) results in a conservative amino acid change located in the I-Band region of the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00077 in 245890 control chromosomes. The observed variant frequency is approximately 1.24 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.22762A>G has been reported in the literature without strong evidence for causality (Campuzano_2015, Mademont-Soler_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. 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. Multiple laboratories reported the variant with conflicting assessments (3 VUS, 2 likely benign). Based on the evidence outlined above, the variant was classified as likely benign.
Mayo Clinic Laboratories,Mayo Clinic RCV000172380 SCV001713241 uncertain significance not provided 2020-06-25 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000172380 SCV001739794 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics, Academic Medical Center RCV000154645 SCV001917536 benign not specified no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000172380 SCV001953665 likely benign not provided no assertion criteria provided clinical testing

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