ClinVar Genomic variation as it relates to human health

c.49189delG: p.Glu16397ArgfsX47 (E16397RfsX47) in exon 230 of the TTN gene (NM_001256850.1). The normal sequence with the base that is deleted in braces is: CCGG{G}AGGA. Although the c.49189delG mutation in the TTN gene has not been reported to our knowledge, this mutation causes a shift in reading frame starting at codon Glutamic acid 16397, changing it to an Arginine, and creating a premature stop codon at position 47 of the new reading frame, denoted p.Glu16397ArgfsX47. 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. Other truncating TTN variants have been reported in approximately 3% of control alleles (Herman D et al., 2012). However, c.49189delG 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, c.49189delG in the TTN gene is interpreted as a disease-causing mutation. The variant is found in DCM-CRDM panel(s).

The TTN c.54112del, p.Glu18038ArgfsTer47 variant (rs794729325) has been previously identified in a single individual included in a cohort of dilated cardiomyopathy patients (Gigli 2019). It has also been identified in persons referred for testing as described in ClinVar (Variation ID: 202452). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift in exon 281 by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Exon 281 is spliced into 100% of TTN transcripts and encodes a segment of the A-band, a critical region of the TTN protein that interacts with myosin and which is disproportionately enriched with truncating variants in individuals affected with dilated cardiomyopathy (Roberts 2015, Schafer 2017). Based on available information, the p.Glu18038ArgfsTer47 variant is considered to be pathogenic. References: Gigli M et al. Genetic Risk of Arrhythmic Phenotypes in Patients With Dilated Cardiomyopathy. J Am Coll Cardiol. 2019 Sep 17;74(11):1480-1490. PMID: 31514951 Roberts AM et al. Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease. Sci Transl Med. 2015; 7(270): 270ra6. PMID: 25589632. Schafer S et al. Titin-truncating variants affect heart function in disease cohorts and the general population. Nat Genet. 2017;49(1):46-53. PMID: 27869827. Begay RL et al. Role of Titin Missense Variants in Dilated Cardiomyopathy. J Am Heart Assoc. 2015 Nov 13;4(11). PMID: 26567375. Herman DS et al. Truncations of titin causing dilated cardiomyopathy. N Engl J Med. 2012 Feb 16;366(7):619-28. PMID: 22335739. Linke WA and Hamdani N. Gigantic business: titin properties and function through thick and thin. Circ Res 2014; 114(6): 1052-1068. PMID: 24625729.

This sequence change creates a premature translational stop signal (p.Glu18038Argfs*47) 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 premature translational stop signal has been observed in individual(s) with clinical features of TTN-related conditions (PMID: 31514951; Invitae). ClinVar contains an entry for this variant (Variation ID: 202452). 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.

The c.26917delG variant, located in coding exon 107 of the TTN gene, results from a deletion of one nucleotide at nucleotide position 26917, causing a translational frameshift with a predicted alternate stop codon (p.E8973Rfs*47). 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 has been reported (as NM_001267550.2:c.54112delG p.E18038Rfs*47) in an individual with dilated cardiomyopathy (DCM) (Gigli M et al. J Am Coll Cardiol, 2019 09;74:1480-1490). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation.

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 a known mechanism of disease for this gene. (I) 0104 - Dominant Negative is likely a mechanism of disease for this gene since not all truncated transcripts in dilated cardiomyopathy (DCM) undergo nonsense mediated decay (PMID: 25589632). (I) 0108 - This gene is known to be associated with both recessive and dominant disease (OMIM). (I) 0112 - Variants in this gene are known to have reduced penetrance of PTC variants in DCM (PMID: 25589632). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (exon 280 of 363). (SP) 0251 - Variant is heterozygous. (I) 0301 - Variant is absent from gnomAD. (SP) 0703 - Comparable variants have moderate previous evidence for pathogenicity. Other variants predicted to cause NMD have been reported as pathogenic in multiple individuals (ClinVar). (SP) 0802 - Moderate previous evidence of pathogenicity in unrelated individuals. The variant has been previously reported in patients with cardiovascular conditions (ClinVar). (SP) 0905 - No segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1206 - This variant has been shown to be paternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign