ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.25619C>T (p.Ser8540Phe)

gnomAD frequency: 0.00045  dbSNP: rs201523784
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Total submissions: 14
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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 RCV000172686 SCV000055046 likely benign not provided 2013-06-24 criteria provided, single submitter research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000040032 SCV000063723 uncertain significance not specified 2015-12-14 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Ser7296Phe va riant in TTN has been identified by our laboratory in 1 infant with unspecified cardiomyopathy, 1 Ashkenazi Jewish adult with HCM, and in 1 Caucasian adult with DCM who also carried a likely pathogenic variant in TTN. In addition, this vari ant has been identified in 54/66002 European chromosomes by the Exome Aggregatio n Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs201523784). Serine ( Ser) at position 7296 is not conserved in mammals or evolutionarily distant spec ies and 4 species (hedgehog, tenrec, Southern platyfish and zebrafish) carry a p henylalanine (Phe) at this position, raising the possibility that this change ma y be tolerated. Additional computational tools do not provide strong support for or against and impact to the protein. In summary, while the clinical significan ce of the p.Ser7296Phe variant is uncertain, its frequency and the presence of t he variant amino acid in other species suggest that it is more likely to be beni gn.
GeneDx RCV000172686 SCV000238364 likely benign not provided 2021-04-06 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 23861362, 27841875)
Invitae RCV001081212 SCV000286530 likely benign Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2024-01-31 criteria provided, single submitter clinical testing
Eurofins Ntd Llc (ga) RCV000040032 SCV000336323 likely benign not specified 2017-06-02 criteria provided, single submitter clinical testing
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute RCV000853460 SCV000996371 likely benign Hypertrophic cardiomyopathy 2017-01-25 criteria provided, single submitter research This variant has been identified as part of our research program. Refer to the 'condition' field for the phenotype of the proband(s) identified with this variant. For further information please feel free to contact us.
Illumina Laboratory Services, Illumina RCV001132881 SCV001292560 uncertain significance Early-onset myopathy 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.
Illumina Laboratory Services, Illumina RCV001132882 SCV001292561 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 Laboratory Services, Illumina RCV001136308 SCV001296137 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 Laboratory Services, Illumina RCV001136309 SCV001296138 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 Laboratory Services, Illumina RCV001136310 SCV001296139 uncertain significance Autosomal recessive 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000040032 SCV001362770 benign not specified 2021-04-20 criteria provided, single submitter clinical testing Variant summary: TTN c.21887C>T (p.Ser7296Phe) results in a non-conservative amino acid change located in the I-band of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00058 in 248154 control chromosomes, predominantly at a frequency of 0.00065 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 slightly higher the estimated maximal expected allele frequency 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.21887C>T in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrences with other pathogenic variants have been reported (ALMS1 c.11629C>T, p.Gln3877X; MYH7 c.2539A>G , p.Lys847Glu), providing supporting evidence for a benign role. Seven 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 (Likely benign/benign n=5, VUS n=2). Based on the evidence outlined above, the variant was classified as benign.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV003149643 SCV003838650 benign Cardiomyopathy 2021-06-09 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000172686 SCV004155254 uncertain significance not provided 2022-11-01 criteria provided, single submitter clinical testing TTN: PM2, BP4

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