Submissions for variant NM_001267550.2(TTN):c.43727_43728del (p.Glu14576fs)

dbSNP: rs794729316

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000184302	SCV000236927	uncertain significance	not provided	2014-04-28	criteria provided, single submitter	clinical testing	c.38804_38805delAA: p.Glu12935GlyfsX2 (E12935GfsX2) in exon 186 of the TTN gene (NM_001256850.1). The normal sequence with the bases that are deleted in braces is: TCAG{AA}GCTA.The c.38804_38805delAA variant in the TTN gene has not been reported previously as a disease-causing mutation or as a benign polymorphism, to our knowledge. c.38804_38805delAA causes a shift in reading frame starting at codon Glutamic acid 12935, changing it to a Glycine, and creating a premature stop codon at position 2 of the new reading frame, denoted p.Glu12935GlyfsX2. This mutation is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. However, other truncating TTN variants have been reported in approximately 3% of control alleles (Herman D et al., 2012). Furthermore, c.38804_38805delAA is not located in the A-band region of TTN, where the majority of truncating mutations associated with DCM have been reported (Herman D et al., 2012). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in CARDIOMYOPATHY panel(s).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004786506	SCV005399089	likely pathogenic	Dilated cardiomyopathy 1G	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely Pathogenic. Following criteria are met: 0103 - Loss of function is known mechanism of disease in this gene. In addition, dominant-negative is also a suggested mechanism as not all truncated transcripts in dilated cardiomyopathy (DCM) undergo nonsense mediated decay (PMID: 25589632). (I) 0108 - This gene is associated with both recessive and dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Null variants have been reported to have incomplete penetrance in DCM (PMID: 25589632, 28045975). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0600 - Variant is located in the annotated I-band whose exon has a PSI of 100 (PMID: 25589632). (I) 0703 - Other NMD-predicted variants comparable to the one identified in this case have moderate previous evidence for pathogenicity (ClinVar). (SP) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. It has been identified in at least two DCM patients (ClinVar). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 0112 - The condition associated with this gene has incomplete penetrance. TTN NMD-predicted variants have been reported to have incomplete penetrance for DCM (PMIDs: 25589632, 28045975). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000223721	SCV000280550	uncertain significance	not specified	2015-03-18	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.Glu12935GlyfsX2 (c.38804_38805delAA, E12935GfsX2) in exon 186 of the TTN gene (NM_001256850.1) Given the lack of case data, the location of the variant, and the fact that 3% of individuals in the general population have a variant of this type in TTN, we consider this a variant of uncertain significance. The variant is novel. This two nucleotide deletion causes a change in the reading frame which leads to a premature stop codon two codons downstream from the deletion. Variants like this may lead to truncated protein products or no produced protein, due to nonsense-mediated decay. 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. 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 not located in the A-band region of titin. 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. 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. This variant is not listed in the NHLBI Exome Sequencing Project dataset. However, since current next generation sequencing methods do not do a good job of calling small indels like this, we cannot trust that it is not in this dataset.