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

dbSNP: rs774395395

Total submissions: 5

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; Autosomal recessive limb-girdle muscular dystrophy type 2J	2022-08-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Pro21563Leufs*10) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy (PMID: 32880476). ClinVar contains an entry for this variant (Variation ID: 235071). 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	RCV000223910	SCV000280555	uncertain significance	not specified	2012-12-01	flagged submission	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