ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.57331C>T (p.Arg19111Ter) (rs72646831)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000157562 SCV000064082 likely pathogenic Primary dilated cardiomyopathy 2013-04-17 criteria provided, single submitter clinical testing The Arg16543X variant in TTN has not been reported in the literature but has bee n identified by our laboratory in one Egyptian individual with DCM (LMM unpublis hed data). The variant is listed in dbSNP with a frequency of 1/376 chromosomes (this data represents a clinical cohort) and was absent from European American and African American chromosomes by the NHLBI Exome Sequencing Project (http://e; dbSNP rs72646831). This nonsense variant leads to a pr emature termination codon at position 16543, which is predicted to lead to a tru ncated or absent protein. Truncating variants in TTN are strongly associated wit h DCM (Herman 2012). In summary, the Arg16543X variant is likely to be pathogeni c, but additional information is needed to fully assess its clinical significanc e.
GeneDx RCV000184240 SCV000236862 pathogenic not provided 2014-03-20 criteria provided, single submitter clinical testing p.Arg17470Stop (CGA>TGA): c.52408 C>T in exon 244 of the TTN gene (NM_001256850.1). R17470X is predicted to cause loss of normal protein function either due to production of an abnormal, prematurely truncated protein, or by absence of protein product due to nonsense mediated mRNA decay. Other truncating TTN variants have been reported in approximately 3% of control alleles (Herman D et al., 2012). However, R17470X is located in the A-band region of titin, where the majority of truncating mutations associated with DCM have been reported (Herman D et al., 2012). Furthermore, R17470X was not observed in approximately 6,200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.In summary, R17470X in the TTN gene is interpreted as a disease-causing mutation. The variant is found in CARDIOMYOPATHY panel(s).
Blueprint Genetics RCV000184240 SCV000928044 pathogenic not provided 2018-11-08 criteria provided, single submitter clinical testing
Invitae RCV001213420 SCV001385049 pathogenic Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2020-06-19 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the TTN gene (p.Arg19111*). While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with dilated cardiomyopathy (PMID: 22335739, 31514951). ClinVar contains an entry for this variant (Variation ID: 47121). 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.
Blueprint Genetics RCV000157562 SCV000207308 likely pathogenic Primary dilated cardiomyopathy 2014-09-29 no assertion criteria provided clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000223733 SCV000280553 uncertain significance not specified 2015-07-22 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Arg17470Stop (R17470X; c.52408 C>T) in the TTN gene This variant produces a premature stop codon in exon 244 of the TTN gene, and is expected to result in production of an abnormal, prematurely truncated protein or an absence of protein product due to nonsense mediated mRNA decay. The Arg17470Stop variant has been reported to segregate with disease in 3 individuals in one family diagnosed with DCM (a father and his two children) at ages 35, 48, and 40 (Herman et al. 2012). This is the only case data available. Truncating TTN variants have been shown by Herman et al. (2012) to be present in 27% of patients with familial dilated cardiomyopathy (DCM) versus approximately 1% of patients with hypertrophic cardiomyopathy (HCM) and 3% of controls. Herman et al. observed strong cosegregation (lod score, 9.3) of nonsense and frameshift variants with clinical status among 60 members of 16 families affected by DCM, indicating an odds of approximately 1 in 10^9 that the segregation of these TTN variants occurred by chance. However, the presence of truncating TTN variants in controls indicates that not all such variants can be presumed to be pathogenic. Another word of caution: Norton et al. (2013, Ray Hershberger’s group) found that not all TTN truncating variants segregate with disease. Herman et al. reported that TTN truncating mutations found in subjects with dilated cardiomyopathy (versus those found in subjects without the disease) were nonrandomly distributed within titin: they were overrepresented in the A-band region. Our patient’s variant is also located in the A-band region, according to the GeneDx report. In total the variant has not been seen in ~6000 individuals from population datasets. It is not listed in the NHLBI Exome Sequencing Project (ESP) dataset, which currently includes variant calls on ~4000 Caucasian and ~2000 African American individuals. None of these individuals are ancestry-matched to our patient, whose ancestry is Mexican. The phenotype of the ESP individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. It is not present in 1000 Genomes (as of March 26, 2014). It is listed in dbSNP as rs72646831, and appears to have been submitted by Robert Livingston’s lab at the University of Washington.

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