ClinVar Miner

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

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Total submissions: 19
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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 RCV000154101 SCV000051347 likely benign not provided 2013-06-24 criteria provided, single submitter research
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.
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.
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)
Ambry Genetics RCV000246075 SCV000318091 likely benign Cardiovascular phenotype 2020-08-31 criteria provided, single submitter clinical testing Other strong data supporting benign classification
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000154101 SCV000334945 uncertain significance not provided 2015-09-03 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000369218 SCV000425157 benign Tibial muscular dystrophy 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
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 RCV000986946 SCV000425159 uncertain significance Dilated cardiomyopathy 1G 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV000366063 SCV000425160 uncertain significance Myopathy, early-onset, with fatal cardiomyopathy 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV000271482 SCV000425161 benign Myopathy, myofibrillar, 9, with early respiratory failure 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Invitae RCV001083564 SCV000555413 likely benign Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2020-12-03 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000040180 SCV000597709 uncertain significance not specified 2016-11-22 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000040180 SCV000605500 uncertain significance not specified 2017-03-11 criteria provided, single submitter clinical testing
Mendelics RCV000986946 SCV001136105 benign Dilated cardiomyopathy 1G 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000154101 SCV001153191 uncertain significance not provided 2016-06-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000040180 SCV001372255 likely benign not specified 2021-07-27 criteria provided, single submitter clinical testing Variant summary: TTN c.3100G>A (p.Val1034Met) results in a conservative amino acid change located in the near Z-disk region (Ig-like domain) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5 splicing donor site. Two predict the variant weakens a 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00081 in 250400 control chromosomes, predominantly at a frequency of 0.0011 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 approximately 2 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 a benign polymorphism found primarily in populations of Non-Finnish European origin. c.3100G>A has been reported in the literature in individuals affected with various phenotypes including end-stage dilated cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy and limb gridle muscular dystrophy (e.g. Roberts_2015, Haas_2015, Lopes_2013, Vasli_2012). These reports 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. Eleven ClinVar submitters (evaluation after 2014) cite the variant as benign (n=2), likely benign (n=2) and uncertain significance (n=7). Based on the evidence outlined above, the variant was classified as likely benign.

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