Submissions for variant NM_001267550.2(TTN):c.99063del (p.Lys33021fs)

dbSNP: rs1445687820

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000691316	SCV000819092	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-10-11	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys33021Asnfs*40) 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 present in population databases (no rsID available, gnomAD 0.006%). 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: 570461). 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.
GeneDx	RCV001008990	SCV001168799	likely pathogenic	not provided	2018-08-06	criteria provided, single submitter	clinical testing	The c.94140delA variant in the TTN gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.94140delA variant causes a frameshift starting with codon Lysine 31380, changes this amino acid to an Asparagine residue, and creates a premature Stop codon at position 40 of the new reading frame, denoted p.Lys31380AsnfsX40. This variant, located within the A-band region of the protein, is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.94140delA variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret c.94140delA as a likely pathogenic variant.
Ambry Genetics	RCV002369860	SCV002670139	pathogenic	Cardiovascular phenotype	2021-01-29	criteria provided, single submitter	clinical testing	The c.71868delA pathogenic mutation, located in coding exon 181 of the TTN gene, results from a deletion of one nucleotide at nucleotide position 71868, causing a translational frameshift with a predicted alternate stop codon (p.K23956Nfs*40). 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 alteration has been observed in at least one individual with a personal and/or family history that is consistent with TTN-related disease (Ambry internal data). In addition, 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.
PreventionGenetics, part of Exact Sciences	RCV003892539	SCV004708280	likely pathogenic	TTN-related condition	2023-12-02	criteria provided, single submitter	clinical testing	The TTN c.99063delA variant is predicted to result in a frameshift and premature protein termination (p.Lys33021Asnfs*40). This variant occurs within the A-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. However, a large number of truncating variants within this exon have been reported individuals with autosomal dominant dilated cardiomyopathy (Supplementary Appendix Table 6, Herman DS et al. 2012. PubMed ID: 22335739). This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD. 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, many cases of recessive TTN-related myopathies in which the individual is compound heterozygous for two loss of function variants in TTN have also been reported (See Ceyhan-Birsoy O. et al. 2013. PMID: 23975875; Chauveau C et al. 2014. PMID: 24105469; Evilä A et al. 2016. PMID: 27796757; Ge et al. 2019. PubMed ID: 31053406).. Therefore, the c.99063delA (p.Lys33021Asnfs*40) variant is interpreted as likely pathogenic for autosomal dominant and recessive TTN-related disorders.