ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.64688del (p.Pro21563fs) (rs774395395)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000246037 SCV000317879 likely pathogenic Cardiovascular phenotype 2013-01-09 criteria provided, single submitter clinical testing
Invitae RCV000528511 SCV000642451 likely pathogenic Dilated cardiomyopathy 1G 2017-06-21 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Pro21563Leufs*10) in the TTN gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with a TTN-related disease. ClinVar contains an entry for this variant (Variation ID: 235071). This variant is found in the A-band of this gene. While this particular variant has not been reported in the literature, truncating variants in the A-band of TTN are significantly overrepresented in patients with dilated cardiomyopathy and are considered to be likely pathogenic for the disease (PMID: 25589632) 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.
Invitae RCV001377021 SCV001574243 likely pathogenic Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2017-06-19 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Pro21563Leufs*10) in the TTN gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with a TTN-related disease. ClinVar contains an entry for this variant (Variation ID: 235071). This variant is found in the A-band of this gene. While this particular variant has not been reported in the literature, truncating variants in the A-band of TTN are significantly overrepresented in patients with dilated cardiomyopathy and are considered to be likely pathogenic for the disease (PMID: 25589632) 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 RCV000223910 SCV000280555 uncertain significance not specified 2012-12-01 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. c.56984delC in TTN (frameshift) The c.56984delC frameshift variant has not been previously reported in association with disease. It is a type of truncating variant, however, that has been seen with relatively high frequency in patients with DCM (Herman et al. 2012). This one nucleotide deletion, located in exon 259 (coding exon 258) of the TTN gene, results in a translational frameshift with a predicted alternate stop codon at position 19004. Ambry notes that frameshifts are typically deleterious in any gene (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med 2008;10:294). Furthermore, 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. 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. TTN truncating mutations found in subjects with dilated cardiomyopathy (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 also located in the A-band region. However, we are classifying it as a VUS, probably disease-causing, since this same type of variant can be seen in controls.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000786259 SCV000925010 uncertain significance not provided 2013-01-07 no assertion criteria provided provider interpretation

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