ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.3100G>A (p.Val1034Met) (rs142951505)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 17
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000040180 SCV000605500 uncertain significance not specified 2017-03-11 criteria provided, single submitter clinical testing
Ambry Genetics RCV000246075 SCV000318091 uncertain significance Cardiovascular phenotype 2013-07-17 criteria provided, single submitter clinical testing
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000154101 SCV000051347 likely benign not provided 2013-06-24 criteria provided, single submitter research
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000209217 SCV000189680 uncertain significance Primary dilated cardiomyopathy 2014-10-08 criteria provided, single submitter research This TTN truncating variant (TTNtv) was identified in three individuals in this cohort and is located in an exon that is highly expressed in the heart. In the seven cohorts assessed, TTNtv were found in 14% of ambulant DCM, 22% end-stage or familial DCM, and 2% controls. Heterozygous nonsense, frameshift and canonical splice-disrupting variants found in constitutive and other highly utilised exons are highly likely to be pathogenic when identified in individuals with phenotypically confirmed DCM. TTNtv found incidentally in healthy individuals (excluding familial assessment of DCM relatives) are thought to have low penetrance, particularly when identified in exons that are not constitutively expressed in the heart.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000209217 SCV000189715 uncertain significance Primary dilated cardiomyopathy 2014-10-08 criteria provided, single submitter research This TTN truncating variant (TTNtv) was identified in one individual in this cohort and is located in an exon that is highly expressed in the heart. In the seven cohorts assessed, TTNtv were found in 14% of ambulant DCM, 22% end-stage or familial DCM, and 2% controls. Heterozygous nonsense, frameshift and canonical splice-disrupting variants found in constitutive and other highly utilised exons are highly likely to be pathogenic when identified in individuals with phenotypically confirmed DCM. TTNtv found incidentally in healthy individuals (excluding familial assessment of DCM relatives) are thought to have low penetrance, particularly when identified in exons that are not constitutively expressed in the heart.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000209217 SCV000189724 uncertain significance Primary dilated cardiomyopathy 2014-10-08 criteria provided, single submitter research This TTN truncating variant (TTNtv) was identified in one individual in this cohort and is located in an exon that is highly expressed in the heart. In the seven cohorts assessed, TTNtv were found in 14% of ambulant DCM, 22% end-stage or familial DCM, and 2% controls. Heterozygous nonsense, frameshift and canonical splice-disrupting variants found in constitutive and other highly utilised exons are highly likely to be pathogenic when identified in individuals with phenotypically confirmed DCM. TTNtv found incidentally in healthy individuals (excluding familial assessment of DCM relatives) are thought to have low penetrance, particularly when identified in exons that are not constitutively expressed in the heart.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000154101 SCV000334945 uncertain significance not provided 2015-09-03 criteria provided, single submitter clinical testing
GeneDx RCV000040180 SCV000237696 uncertain significance not specified 2016-11-23 criteria provided, single submitter clinical testing Missense variants in the TTN gene are considered 'unclassified' if they are not previously reported in the literature and do not have >1% frequency in the population to be considered a polymorphism. Research indicates that truncating mutations in the TTN gene are expected to account for approximately 25% of familial and 18% of sporadic idiopathic DCM; however, truncating variants in the TTN gene have been reported in approximately 3% of reported control alleles. There has been little investigation into non-truncating variants. (Herman D et al. Truncations of titin causing dilated cardiomyopathy. N Eng J Med 366:619-628, 2012)
Genetic Services Laboratory, University of Chicago RCV000040180 SCV000597709 uncertain significance not specified 2016-11-22 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000314508 SCV000425156 uncertain significance Hypertrophic cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000369218 SCV000425157 benign Distal myopathy Markesbery-Griggs type 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000402487 SCV000425158 uncertain significance Limb-Girdle Muscular Dystrophy, Recessive 2016-06-14 criteria provided, single submitter clinical testing Vasli et al. (2012) reported the c.3100G>A (p.Val1034Met) variant in a compound heterozygous state in one patient with limb-girdle muscular dystrophy. Control data are unavailable for this variant, which is reported at a frequency of 0.002137 in the European (Finnish) population of the Exome Aggregation Consortium. The evidence for this variant is limited to a single patient. The p.Val1034Met variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for limb-girdle muscular dystrophy.
Illumina Clinical Services Laboratory,Illumina RCV000310978 SCV000425159 uncertain significance Dilated Cardiomyopathy, Dominant 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000366063 SCV000425160 uncertain significance Myopathy, early-onset, with fatal cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000271482 SCV000425161 benign Hereditary myopathy with early respiratory failure 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000469396 SCV000555413 likely benign Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2017-12-19 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000040180 SCV000063871 uncertain significance not specified 2014-07-23 criteria provided, single submitter clinical testing The Val1034Met variant in TTN has been reported in 1 individual with limb girdle muscular dystrophy (Vasli 2012). This variant has also been identified by our l aboratory in 2 individuals (1 adult & 1 infant) with DCM and 1 infant with HCM, but is also present in 0.1% (10/8600) of European American chromosomes by the NH LBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs1429515 05). The population frequency of this variant raises the possibility that it is benign, but is too low to confidently rule out a disease causing role. The varia nt is located in the last base of the exon, which is part of the 5? splice regio n, and computational tools suggest an impact to splicing; however, this informat ion is not predictive enough to determine pathogenicity (their accuracy is unkno wn). In summary, the clinical significance of the Val1034Met variant is uncertai n.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.