Submissions for variant NM_001267550.2(TTN):c.40723+1del

dbSNP: rs876658058

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000214841	SCV000272643	uncertain significance	not specified	2016-01-13	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The c.33109+1de l variant in TTN has not been previously reported in individuals with cardiomyop athy or in large population studies. This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered sp licing leading to an abnormal or absent protein. Truncating variants in TTN are strongly associated with DCM if they are located in an exon that is highly expre ssed in the heart (Roberts 2015) and splice variants often lead to truncation. T he c.33109+1del variant is located in the highly expressed exon 170 of the I-ban d. While there is some suspicion for a pathogenic role, its significance remain s uncertain due to the lack of certainty on whether it leads to truncation combi ned with the architecture of this part of the TTN protein (multiple repeated sub -domains).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000543496	SCV000643126	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-03-09	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 sequence change affects a splice site in intron 221 of the TTN gene. It is expected to disrupt RNA splicing and likely results in a truncated or disrupted TTN protein. This variant is present in population databases (no rsID available, gnomAD 0.0009%). 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: 229431). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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).
GeneDx	RCV003324733	SCV004030635	uncertain significance	not provided	2023-08-24	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (gnomAD); Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown; Located in a region of TTN within the I-band in which the majority of loss of function variants are significantly associated with autosomal dominant titinopathies (Deo et al., 2016; Schafer et al., 2017); This variant is associated with the following publications: (PMID: 27535533, 26582918, 27625338, 27869827)
Ambry Genetics	RCV003352805	SCV004053246	uncertain significance	Cardiovascular phenotype	2023-07-18	criteria provided, single submitter	clinical testing	The c.13528+1delG intronic variant, located in intron 48 of the TTN gene, results from a deletion of one nucleotide within intron 48 of the TTN gene. Exon 48 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%). This alteration disrupts the canonical splice site and is expected to cause aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. However, although direct evidence is unavailable, this alteration is predicted to result in an in-frame transcript that is not expected to trigger nonsense-mediated mRNA decay. The exact functional effect of the predicted splice impact is unknown. This nucleotide position is highly conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV004532765	SCV004120264	likely pathogenic	TTN-related disorder	2023-03-09	criteria provided, single submitter	clinical testing	The TTN c.40723+1delG variant is predicted to result in a deletion affecting a canonical splice site. To our knowledge, this variant has not been reported in the literature. This variant is located in the TTN protein I-band region. RNA sequencing studies from heart tissue indicate this exon is commonly included in TTN mRNA transcripts (Exon 221, PSI of 95%-100%, Roberts 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 et al. 2015. PMID: 25589632; Herman et al. 2012. PMID: 22335739). However, 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 et al. 2013. PMID: 23975875; Chauveau et al. 2014. PubMed ID: 24105469; Evilä et al. 2016. PubMed ID: 27796757; Ge et al. 2019. PubMed ID: 31053406). This variant is reported in 1 of ~240,000 alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-179505266-AC-A). This variant is interpreted as likely pathogenic for both autosomal recessive and dominant TTN-related disorders.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV003352805	SCV006065404	uncertain significance	Cardiovascular phenotype	2025-04-09	criteria provided, single submitter	clinical testing	PVS1_mod, PM2, PS4_supp