ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.2841G>T (p.Ser947=)

dbSNP: rs774074192
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Total submissions: 4
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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 RCV000209067 SCV000189744 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.
Eurofins Ntd Llc (ga) RCV000727789 SCV000855192 uncertain significance not provided 2017-11-01 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001853339 SCV002168288 uncertain significance Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2023-04-13 criteria provided, single submitter clinical testing In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant is located in the Z band of TTN (PMID: 25589632). Variants in this region may be clinically relevant, but have not been definitively shown to cause cardiomyopathy or neuromuscular disease (PMID: 27493940, 32778822). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 223342). This variant has been observed in individual(s) with cardiac disease (PMID: 25589632). This variant is not present in population databases (gnomAD no frequency). This sequence change affects codon 947 of the TTN mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the TTN protein. This variant also falls at the last nucleotide of exon 17, which is part of the consensus splice site for this exon.
Ambry Genetics RCV002426984 SCV002742860 uncertain significance Cardiovascular phenotype 2022-03-14 criteria provided, single submitter clinical testing The c.2703G>T variant (also known as p.S901S) is located in coding exon 15 of the TTN gene. This variant results from a G to T substitution at nucleotide position 2703. This nucleotide substitution does not change the serine at codon 901. However, this change occurs in the last base pair of coding exon 15, which makes it likely to have some effect on normal mRNA splicing. This variant (referred to as c.2841G>T) has been detected an an individual from a population-based cohort; however, details were limited (Roberts AM et al. Sci Transl Med, 2015 Jan;7:270ra6). This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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