ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.62506C>T (p.Arg20836Ter)

dbSNP: rs757231565
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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 RCV000209294 SCV000189733 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.
Ambry Genetics RCV000621391 SCV000736604 likely pathogenic Cardiovascular phenotype 2020-01-24 criteria provided, single submitter clinical testing The p.R11771* variant (also known as c.35311C>T), located in coding exon 131 of the TTN gene, results from a C to T substitution at nucleotide position 35311. This exon is located in the A-band region of the N2-B isoform of the titin protein and is constitutively expressed in TTN transcripts (percent spliced in or PSI 100%). This changes the amino acid from an arginine to a stop codon within coding exon 131. This variant has been reported in the Framingham Heart Study offspring cohort with alternate nomenclature (p.R20836*, c.62506C>T); however, clinical details were limited (Roberts AM et al., Sci Transl Med 2015 Jan; 7(270):270ra6). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. While truncating variants in TTN are present in 1-3% of the general population, truncating variants in the A-band are the most common cause of dilated cardiomyopathy (DCM) (Herman DS et al. N. Engl. J. Med., 2012 Feb;366:619-28; Roberts AM et al. Sci Transl Med, 2015 Jan;7:270ra6). TTN truncating variants encoded in constitutive exons (PSI >90%) have been found to be significantly associated with DCM regardless of their position in titin (Schafer S et al. Nat. Genet., 2017 01;49:46-53). As such, this alteration is classified as likely pathogenic.
GeneDx RCV001564576 SCV001787761 pathogenic not provided 2023-08-14 criteria provided, single submitter clinical testing Reported in one individual from the Framingham Heart Study offspring cohort, although it is unclear if this individual was affected (Roberts et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Located in the A-band region of TTN in which the majority of loss of function variants have been associated with autosomal dominant titinopathies (Herman et al., 2012); This variant is associated with the following publications: (PMID: 22335739, 32528171, 25589632)
Invitae RCV002517417 SCV003276868 pathogenic Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2023-11-24 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg20836*) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. This variant is present in population databases (rs757231565, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with autosomal dominant dilated cardiomyopathy (Invitae). ClinVar contains an entry for this variant (Variation ID: 223258). This variant is located in the A band of TTN (PMID: 25589632). Truncating variants in this region are significantly overrepresented in patients affected with dilated cardiomyopathy (PMID: 25589632). Truncating variants in this region have also been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875). For these reasons, this variant has been classified as Pathogenic.

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