ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.57769C>T (p.Arg19257Ter) (rs794729275)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000184241 SCV000236863 likely pathogenic not provided 2014-04-02 criteria provided, single submitter clinical testing )p.Arg17616Stop (R17616X) CGA>TGA: c.52846 C>T in exon 245 of the TTN gene (NM_001256850.1). The R17616X mutation in the TTN gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. R17616X is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Other truncating TTN variants have been reported in approximately 3% of control alleles (Herman D et al., 2012). However, R17616X 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). In summary, R17616X in the TTN gene is interpreted as a disease-causing mutation. The variant is found in CARDIOMYOPATHY panel(s).
Ambry Genetics RCV000248842 SCV000320204 likely pathogenic Cardiovascular phenotype 2015-09-22 criteria provided, single submitter clinical testing The p.R10192* variant (also known as c.30574C>T), located in coding exon 122 of the TTN gene, results from a C to T substitution at nucleotide position 30574. This changes the amino acid from an arginine to a stop codon within coding exon 122, and is located in the A-band region of thetitin protein. Truncating alterations in TTN were observed at a significantly higher frequency among patients with dilated cardiomyopathy (DCM), or 54/203 (27%), compared to patients with hypertrophic cardiomyopathy (3 of 231, 1%, P=3x10<sup>-16</sup>) and healthy controls (7 of 249, 3%, P=9x10<sup>-14</sup>). Among families with multiple relatives with DCM, studies also provided strong data demonstrating segregation of TTN truncations with disease (Herman DS et al. N Engl J Med. 2012;366(7):619-28; Pugh TJ et al. Genet Med. 2014;16(8):601-8). The functional mechanism of TTN truncations leading to dilated cardiomyopathy is not well understood; however, truncating alterations are typically deleterious in nature (ACMG Standards and guidelines for the interpretation of sequence variants. Genet Med. 2015;17(5):405-24). As such, the p.R10192* variant is classified as likely pathogenic.
Blueprint Genetics RCV000184241 SCV000927721 likely pathogenic not provided 2018-06-01 criteria provided, single submitter clinical testing
Invitae RCV001378032 SCV001575514 likely pathogenic Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2020-06-18 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the TTN gene (p.Arg19257*). 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 or left ventricular noncompaction (PMID: 28798025, Invitae). ClinVar contains an entry for this variant (Variation ID: 202392). 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). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000223817 SCV000280554 uncertain significance not specified 2014-05-16 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.Arg17616Stop (c.52846 C>T) in the TTN gene (NM_001256850.1) Given that 3% of controls have a vairant like this, the location of the variant within the gene, and the absence in controls, we consider it a variant of uncertain significance, probably disease causing. We do not recommend using this variant to assess risk in healthy relatives. We do recommend tesitng the affected father and any other affected relatives specifically for this variant to help clarify its role in disease. The variant is novel. I could find no online or published references. This substitution creates a premature stop codon. With >300 exons and >34,000 amino acids, TTN has the largest coding sequence in the genome, and the majority of the general population will have at least 1 rare (defined as a mean allele frequency <0.5%) missense or truncating variant at this locus. Truncating TTN variants have been shown by Herman et al. (2012) to be present in 27% of patients with familial dilated cardiomyopathy (DCM). Herman et al. report that they 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, Herman et al (2012) also observed truncating TTN variants in approximately 3% of control individuals. In addition, Norton et al. (2013) showed that not all truncating variants in TTN segregate with disease (DCM) in affected families. Norton et al. identified 6 TTN truncating variants carried by individuals affected with DCM in 7 of 17 DCM families (logarithm of odds, 2.99); 2 of these 7 families also had novel missense variants that segregated with disease. Two additional novel truncating TTN variants did not segregate with DCM. Herman et al (2012) observed that TTN truncating variants found in subjects with DCM (as opposed to 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 located in the A-band region of titin. Thus, while the findings of Herman et al (2012) provide strong evidence that truncating TTN variants contribute to familial DCM, it is still challenging to determine the significance of anyone individual truncating variant. In total the variant has not been seen in ~6500 individuals from publicly available population datasets. The variant is not listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of June 11th, 2014). There is a missense variant at this codon in 1 of 5968 individuals in ESP (p.Arg17616Gln).

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