Submissions for variant NM_001267550.2(TTN):c.41483del (p.Pro13828fs)

dbSNP: rs876657664

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000219662	SCV000271274	likely pathogenic	Primary dilated cardiomyopathy	2015-05-06	criteria provided, single submitter	clinical testing	The p.Pro11260fs variant in TTN has not been previously reported in individuals with cardiomyopathy or in large population studies. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 11260 and leads to a premature termination codon 6 amino acids downstr eam. This alteration is then predicted to lead to a truncated or absent protein. Frameshift and other truncating variants in TTN are strongly associated with DC M if they are located in the exons encoding for the A-band (Herman 2012, Pugh 20 14) and/or are located in an exon that is highly expressed in the heart (Roberts 2015). The p.Pro11260fs variant is located in the I-band in the highly expresse d exon 175. In summary, although additional studies are required to fully establ ish its clinical significance, the p.Pro11260fs variant is likely pathogenic.
Ambry Genetics	RCV000621973	SCV000737317	likely pathogenic	Cardiovascular phenotype	2017-10-13	criteria provided, single submitter	clinical testing	The c.14288delC variant, located in coding exon 53 of the TTN gene, results from a deletion of one nucleotide at nucleotide position 14288, causing a translational frameshift with a predicted alternate stop codon (p.P4763Qfs*6). This exon is located in the I-band region of the N2-B isoform of the titin protein and is constitutively expressed in TTN transcripts (percent spliced in or PSI 100%). 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 Jan;49:46-53). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
Invitae	RCV001046113	SCV001210001	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2022-07-19	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant is located in the I band of TTN (PMID: 25589632). Truncating variants in this region have been shown to be highly prevalent in the general population and unaffected individuals (PMID: 26701604, 22335739). However, truncating variants in this region have also been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875). ClinVar contains an entry for this variant (Variation ID: 228299). This variant has not been reported in the literature in individuals affected with TTN-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Pro13828Glnfs*6) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein.
PreventionGenetics, part of Exact Sciences	RCV003401128	SCV004104257	likely pathogenic	TTN-related condition	2023-02-14	criteria provided, single submitter	clinical testing	The TTN c.41483delC variant is predicted to result in a frameshift and premature protein termination (p.Pro13828Glnfs*6). This variant occurs within the I-band region of the titin protein. RNAseq studies from heart tissue indicate this exon is commonly included in TTN mRNA transcripts (PSI of 100%, Roberts AM et al. 2015. PubMed ID: 25589632; https://cardiodb.org/titin/titin_transcripts.php). TTN truncating variants are reported in 1-2% of presumably healthy individuals, but occur more frequently in exons with low PSI values (Roberts AM et al. 2015. PubMed ID: 25589632; Herman DS et al. 2012. PubMed ID: 22335739). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-179500814-TG-T). Of note, truncating TTN variants in constitutive exons (PSI > 90%) are significantly associated with dilated cardiomyopathy (DCM) irrespective of their position in TTN (Schafer S et al. 2017. PubMed ID: 27869827). In addition, truncating TTN mutations have also been associated with autosomal recessive congenital myopathy (Ceyhan-Birsoy O et al. 2013. PubMed ID: 23975875). Therefore, the c.41483delC (p.Pro13828Glnfs*6) variant is interpreted as likely pathogenic for recessive and dominant TTN-related disorders.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987453	SCV004803479	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-16	criteria provided, single submitter	clinical testing	Variant summary: TTN c.33779delC (p.Pro11260GlnfsX6) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4e-06 in 248406 control chromosomes (gnomAD). To our knowledge, no occurrence of c.33779delC in individuals affected with Limb-Girdle Muscular Dystrophy, Type 2J and no experimental evidence demonstrating its impact on protein function have been reported. Nonsense, frameshift, and canonical splice-site variants in TTN are strongly associated with DCM when they affect exons encoding for the A-band region (PMIDs: 22335739, 24503780) and/or exons constitutively expressed (proportion spliced in [PSI]>0.9) in the primary cardiac isoforms (PMIDs: 25589632, 31216868, 32964742, 27869827), which is the case for this variant (I band with a PSI score of 100%). ClinVar contains an entry for this variant (Variation ID: 228299). Based on the evidence outlined above, the variant was classified as likely pathogenic.