Submissions for variant NM_001267550.2(TTN):c.62909dup (p.Glu20971fs)

dbSNP: rs876657666

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000216412	SCV000271278	likely pathogenic	Primary dilated cardiomyopathy	2015-02-13	criteria provided, single submitter	clinical testing	The p.Glu18403fs variant in TTN has not been previously reported in individuals with cardiomyopathy and was absent in large population studies. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 18403 and leads to a premature termination codon 4 amino a cids downstream. This alteration is then predicted to lead to a truncated or abs ent protein. Frameshift and other truncating variants in TTN are strongly associ ated with DCM, particularly if they are located in the exons encoding for the A- band region of the protein (Herman 2012, Pugh 2014), where this variant is locat ed. In summary, although additional studies are required to fully establish its clinical significance, the p.Glu18403fs variant is likely pathogenic.
Eurofins Ntd Llc (ga)	RCV000732221	SCV000860144	likely pathogenic	not provided	2018-03-20	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000732221	SCV000927501	likely pathogenic	not provided	2017-12-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000795052	SCV000934493	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-05-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu20971Argfs*4) in the TTN gene. 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 (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TTN-related conditions. ClinVar contains an entry for this variant (Variation ID: 228301). 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003150110	SCV003837987	likely pathogenic	Cardiomyopathy	2022-02-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004020606	SCV005020534	likely pathogenic	Cardiovascular phenotype	2024-12-13	criteria provided, single submitter	clinical testing	The c.35714dupC variant, located in coding exon 131 of the TTN gene, results from a duplication of C at nucleotide position 35714, causing a translational frameshift with a predicted alternate stop codon (p.E11906Rfs*4). This exon is located in the A-band region of the N2-B isoform of the titin protein and is constitutively expressed in TTN transcripts (percent spliced in or PSI 100%). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. While truncating variants in TTN are present in 1-3% of the general population, truncating variants in the A-band are the most common cause of dilated cardiomyopathy (DCM) (Herman DS et al. N. Engl. J. Med., 2012 Feb;366:619-28; Roberts AM et al. Sci Transl Med, 2015 Jan;7:270ra6). TTN truncating variants encoded in constitutive exons (PSI >90%) have been found to be significantly associated with DCM regardless of their position in titin (Schafer S et al. Nat. Genet., 2017 01;49:46-53). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Clinical Genomics Laboratory, Washington University in St. Louis	RCV004555858	SCV005045106	likely pathogenic	Dilated cardiomyopathy 1G	2024-03-29	criteria provided, single submitter	clinical testing	The TTN c.62909dup (p.Glu20971ArgfsTer4) variant has been reported in one large scale study, but it was not specified if the identified individual was affected with a TTN-related disorder (Haggerty CM et al., PMID: 31216868). This variant has been reported in the ClinVar database as a germline likely pathogenic variant by five submitters. This variant causes a frameshift by duplicating a single nucleotide, leading to a premature termination codon, which is predicted to lead to nonsense mediated decay. This variant is located in the TTN protein A-band and truncating variants in this region are strongly associated with dilated cardiomyopathy (Rich KA et al., PMID: 32815318; Roberts AM et al., PMID: 25589632). Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as likely pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004555858	SCV005399423	likely pathogenic	Dilated cardiomyopathy 1G	2022-02-02	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: 0102 - Loss of function is known mechanism of disease in this gene. In addition, dominant-negative is also a suggested mechanism. (PMID: 25589632). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance. Variants in this gene that result in a premature truncating codon (PTC) are known to have reduced penetrance in DCM (PMID: 25589632). (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 C-terminal A-band and the exon has a PSI score 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) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals (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) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign