ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.97192+4A>G

gnomAD frequency: 0.00001  dbSNP: rs370069759
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Total submissions: 3
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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 RCV000209317 SCV000189762 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.
Invitae RCV001853341 SCV002316494 uncertain significance Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2022-07-14 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 A band of TTN (PMID: 25589632). Variants in this region may be relevant for cardiac or neuromuscular disorders (PMID: 25589632, 23975875). 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 is not likely to affect RNA splicing. ClinVar contains an entry for this variant (Variation ID: 223355). This variant has not been reported in the literature in individuals affected with TTN-related conditions. This variant is present in population databases (rs370069759, gnomAD 0.008%). This sequence change falls in intron 348 of the TTN gene. It does not directly change the encoded amino acid sequence of the TTN protein. It affects a nucleotide within the consensus splice site.
Ambry Genetics RCV002363049 SCV002665761 uncertain significance Cardiovascular phenotype 2020-08-21 criteria provided, single submitter clinical testing The c.69997+4A>G intronic variant results from an A to G substitution 4 nucleotides after coding exon 175 in the TTN gene. This variant has been reported in the Jackson Heart Study cohort with alternate nomenclature (as NM_001267550.1:c.97192+4A>G); however, clinical details were limited (Roberts AM et al. Sci Transl Med, 2015 Jan;7:270ra6). This nucleotide position is highly 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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