Submissions for variant NM_001267550.2(TTN):c.49648+2del

gnomAD frequency: 0.00003  dbSNP: rs727504851

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000156200	SCV000205916	pathogenic	Primary dilated cardiomyopathy	2019-01-18	criteria provided, single submitter	clinical testing	The c.41944+2delT (also referred to as c.44725+2delT) variant in TTN has been reported in 3 individuals with DCM and 1 individual with LVNC and segregated with disease in 7 affected relatives from 3 families, including 2 affected obligate carriers (Herman 2012, LMM data). It has also been identified in 5/126328 European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and reported in ClinVar (Variation ID #179411). This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing, leading to an abnormal or absent protein. In vivo functional studies also provide some evidence that the c.41944+2delT variant may impact RNA splicing (Herman 2012). Splicing and other truncating variants in TTN are strongly associated with DCM if they impact the exons encoding for the A-band (Herman 2012, Pugh 2014) and/or located in an exon that is highly expressed in the heart (Roberts 2015). This variant affects splicing of exons located in the A-band. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant DCM. ACMG/AMP Criteria applied: PP1_Strong, PVS1_Moderate, PM2, PS3_Supporting, PS4_Suporting.
GeneDx	RCV000184308	SCV000236933	pathogenic	not provided	2022-05-23	criteria provided, single submitter	clinical testing	Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Located in the A-band region of TTN in which the majority of loss of function variants have been associated with autosomal dominant titinopathies (Herman et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30535219, 22335739, 30150400, 32964742, 33874732, 33500567)
Invitae	RCV000705999	SCV000835026	pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change affects a splice site in intron 264 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 (rs727504851, gnomAD 0.005%). Disruption of this splice site has been observed in individuals with dilated cardiomyopathy (PMID: 22335739). It has also been observed to segregate with disease in related individuals. This variant is also known as c.44725+2delT. ClinVar contains an entry for this variant (Variation ID: 179411). 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 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). For these reasons, this variant has been classified as Pathogenic.
Eurofins Ntd Llc (ga)	RCV000184308	SCV000862484	pathogenic	not provided	2018-07-19	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000184308	SCV000928141	pathogenic	not provided	2018-12-27	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170836	SCV001333456	pathogenic	Cardiomyopathy	2021-03-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001266080	SCV001444252	pathogenic	Inborn genetic diseases	2018-12-12	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000184308	SCV002022467	pathogenic	not provided	2022-01-27	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV000184308	SCV002502336	pathogenic	not provided	2022-02-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002415671	SCV002724997	pathogenic	Cardiovascular phenotype	2021-10-14	criteria provided, single submitter	clinical testing	The c.22453+2delT intronic pathogenic mutation results from a deletion of one nucleotide at position c.22453+2, located two nucleotides after coding exon 91 of the TTN gene. Exon 91 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 disrupts the canonical donor splice site of exon 91 and is expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. While loss of function variants in TTN are present in 1-3% of the general population, truncating variants (a category that includes canonical splice site 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 particular alteration (reported as c.44725+2delT) was detected in two probands with dilated cardiomyopathy, segregated with disease phenotype in two families, and was indicated to cause aberrant splicing in RNA studies of tissue from an affected proband (Herman DS et al. N. Engl. J. Med., 2012 Feb;366:619-28). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Fulgent Genetics, Fulgent Genetics	RCV002478464	SCV002799572	pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J; Tibial muscular dystrophy; Myopathy, myofibrillar, 9, with early respiratory failure; Early-onset myopathy with fatal cardiomyopathy; Hypertrophic cardiomyopathy 9	2021-11-17	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000184308	SCV004011268	pathogenic	not provided	2023-05-01	criteria provided, single submitter	clinical testing	TTN: PVS1, PS4:Moderate, PS3:Supporting
PreventionGenetics, part of Exact Sciences	RCV003390850	SCV004121633	pathogenic	TTN-related condition	2022-10-17	criteria provided, single submitter	clinical testing	The TTN c.49648+2delT variant is predicted to result in a deletion affecting a canonical splice site. The c.49648+2delT variant, also reported as c.44725+2delT, is located in the A-band region of the protein in which truncating TTN variants have been found more frequently in dilated cardiomyopathy patients than in controls (Herman D.S. et al. 2012. PubMed ID: 22335739). RNAseq studies from heart tissue indicate this exon is commonly included in TTN mRNA transcripts (PSI of 100%, Roberts A.M. et al. 2015. PMID: 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 A.M. et al. 2015. PMID: 25589632; Herman D.S. et al. 2012. PMID: 22335739). This variant has been reported in individuals with dilated cardiomyopathy, an individual with early-onset atrial fibrillation, and an individual with peripartum cardiomyopathy (Herman D.S. et al 2012. Supplementary Appendix Table 4 PubMed ID: 22335739; Choi SH et al 2018. eTable 5 PubMed ID: 30535219; Akhtar MM et al 2020. Supplementary Table S2 PubMed ID: 32964742; Goli R et al 2021. Supplemental Table 2 PubMed ID: 33874732). Other truncating variants in this exon have previously been reported to be pathogenic for TTN-related disorders (Human Gene Mutation Database). This variant is reported in 0.0040% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-179477885-TA-T). In summary, the c.49648+2delT splice variant is interpreted as pathogenic for recessive and dominant TTN-related disorders.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001170836	SCV004122225	pathogenic	Cardiomyopathy	2023-10-26	criteria provided, single submitter	clinical testing	Variant summary: TTN c.41944+2delT is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Herman_2012). The variant allele was found at a frequency of 1.6e-05 in 244206 control chromosomes. c.41944+2delT has been reported in the literature in individuals affected with Cardiomyopathy (Herman_2012). These data indicate that the variant may be associated with disease. The following publication have been ascertained in the context of this evaluation (PMID: 22335739). Twelve submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GenomeConnect - Invitae Patient Insights Network	RCV001535491	SCV001749434	not provided	Primary dilated cardiomyopathy; Autosomal recessive limb-girdle muscular dystrophy type 2J; Tibial muscular dystrophy; Myopathy, myofibrillar, 9, with early respiratory failure		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 07-27-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.