ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.44281C>T (p.Pro14761Ser) (rs192766485)

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Total submissions: 19
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000209622 SCV000189682 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000154951 SCV000204633 benign not specified 2018-11-09 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx RCV000154951 SCV000237174 likely benign not specified 2017-11-21 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.
Blueprint Genetics RCV000154951 SCV000264280 likely benign not specified 2015-06-25 criteria provided, single submitter clinical testing
Invitae RCV001085058 SCV000542551 likely benign Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2020-12-03 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000725365 SCV000700951 uncertain significance not provided 2018-06-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV000621229 SCV000735436 likely benign Cardiovascular phenotype 2019-12-18 criteria provided, single submitter clinical testing In silico models in agreement (benign);Subpopulation frequency in support of benign classification
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769013 SCV000900386 likely benign Cardiomyopathy 2019-01-25 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000725365 SCV001146406 likely benign not provided 2018-12-29 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001283227 SCV001157839 uncertain significance none provided 2020-07-24 criteria provided, single submitter clinical testing The TTN c.44281C>T p.Pro14761Ser variant (rs192766485; ClinVar Variation ID: 178217) is rare in the general population (<1% allele frequency in the Genome Aggregation Database) and has been reported in a cohort of individuals with dilated cardiomyopathy (Roberts 2015). 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.Pro12193Ser variant cannot be determined with certainty.
Illumina Clinical Services Laboratory,Illumina RCV001130087 SCV001289650 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 RCV001130088 SCV001289651 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 RCV001130089 SCV001289652 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 RCV000415667 SCV001290375 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). 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 RCV001130785 SCV001290376 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000154951 SCV001448577 likely benign not specified 2020-11-02 criteria provided, single submitter clinical testing Variant summary: TTN c.36577C>T (p.Pro12193Ser) results in a non-conservative amino acid change located in the I band domain (https://www.cardiodb.org/titin/titin_transcripts.php) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00066 in 248262 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 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy phenotype (0.00039), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.36577C>T has been reported in the literature in individuals affected with sudden unexplained death/Left Ventricular Non-Compaction (Campuzano_2015). However, this report does not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Twelve ClinVar submitters (evaluation after 2014) cite the variant as likely benign/benign (n=7) or uncertain significance (n=5). Based on the evidence outlined above, the variant was classified as likely benign.
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000415667 SCV000493821 uncertain significance Dilated cardiomyopathy 1G 2015-12-04 no assertion criteria provided clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000415702 SCV000493822 uncertain significance Familial hypertrophic cardiomyopathy 9 2015-12-04 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000725365 SCV001551593 uncertain significance not provided no assertion criteria provided clinical testing The TTN p.Pro12193Ser variant was not identified in the literature but was identified in dbSNP (ID: rs192766485), LOVD 3.0 and ClinVar (classified as uncertain significance by Invitae, Ambry Genetics, EGL Genetics and three other laboratories, as likely benign by Blueprint Genetics and GeneDx and as benign by Laboratory for Molecular Medicine). The variant was identified in control databases in 181 of 279630 chromosomes at a frequency of 0.0006473 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 142 of 127884 chromosomes (freq: 0.00111), Other in 7 of 7120 chromosomes (freq: 0.000983), Latino in 24 of 35264 chromosomes (freq: 0.000681) and African in 8 of 24182 chromosomes (freq: 0.000331), but was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), or South Asian populations. The p.Pro12193 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The p.Pro12193Ser variant occurs in the last base of the exon; this position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. However, three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a greater than 10% difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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