ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.72931A>G (p.Thr24311Ala) (rs56201325)

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Total submissions: 17
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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 RCV000040588 SCV000051708 benign not specified 2013-06-24 criteria provided, single submitter research
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000040588 SCV000064279 benign not specified 2015-03-30 criteria provided, single submitter clinical testing p.Thr21743Ala in exon 275 of TTN: This variant is not expected to have clinical significance because it has been identified in 0.9% (60/6610) of Finnish chromos omes and 0.7% (477/65890) European chromosomes, including two homozygous individ uals, by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs56201325).
Genetic Services Laboratory,University of Chicago RCV000118779 SCV000153340 likely benign not provided 2015-02-10 criteria provided, single submitter clinical testing
GeneDx RCV000040588 SCV000237520 benign not specified 2016-11-28 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics RCV000249950 SCV000318899 benign Cardiovascular phenotype 2016-11-02 criteria provided, single submitter clinical testing General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000040588 SCV000332032 likely benign not specified 2015-06-10 criteria provided, single submitter clinical testing
Invitae RCV001083516 SCV000555077 benign Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2019-12-31 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000040588 SCV000616138 benign not specified 2016-12-08 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769952 SCV000901378 benign Cardiomyopathy 2018-01-29 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000118779 SCV001152756 likely benign not provided 2019-12-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000040588 SCV001159345 uncertain significance not specified 2018-11-24 criteria provided, single submitter clinical testing The TTN c.65227A>G; p.Thr21743Ala variant (rs56201325; ClinVar Variation ID: 47318) 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.Thr21743Ala 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.
Illumina Clinical Services Laboratory,Illumina RCV001131595 SCV001291226 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.
Illumina Clinical Services Laboratory,Illumina RCV001131996 SCV001291647 likely benign 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Clinical Services Laboratory,Illumina RCV001131997 SCV001291648 uncertain significance Limb-girdle muscular dystrophy, type 2J 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 RCV001131998 SCV001291649 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 RCV001131999 SCV001291650 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.
Integrated Genetics/Laboratory Corporation of America RCV000040588 SCV001426966 likely benign not specified 2020-07-06 criteria provided, single submitter clinical testing Variant summary: TTN c.65227A>G (p.Thr21743Ala) results in a non-conservative amino acid change located in the A-band region (cardiodb.org) 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 0.004 in 244666 control chromosomes in the gnomAD database, including 3 homozygotes. The observed variant frequency is approximately 6.4- fold 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.65227A>G has been reported in the literature in individuals affected with Cardiomyopathy (examples- Lopes_2013, Pugh_2014, Campuzano_2015). 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. 13 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 (benign, n=7; likely benign, n=4; uncertain significance, n=2). Based on the evidence outlined above, the variant was classified as likely benign.

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