Submissions for variant NM_001267550.2(TTN):c.86821+2T>A

gnomAD frequency: 0.00005  dbSNP: rs397517735

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000040727	SCV000064418	likely pathogenic	Primary dilated cardiomyopathy	2019-01-18	criteria provided, single submitter	clinical testing	The c.79117+2T>A variant in TTN has been identified in 4 individuals with DCM and segregated with the disease in 5 affected relatives from 3 families (Norton 2013, Herman 2012, LMM data). It has also been identified 1/21992 African chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, the quality of this region was low. This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. Splice site variants 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 are located in an exon that is highly expressed in the heart (Roberts 2015). The c.79117+2T>A variant is located in A-band. Loss of function of the TTN gene is an established disease mechanism in autosomal dominant DCM. ACMG/AMP criteria applied: PVS1_Moderate, PS4_Moderate, PP1_Moderate.
GeneDx	RCV000184278	SCV000236901	pathogenic	not provided	2023-08-15	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon 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); This variant is associated with the following publications: (PMID: 22335739, 23418287, 30681174, 31402444, 33874732, 36264615, 34731015, 33226272)
Invitae	RCV000627778	SCV000286884	pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 326 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 (rs397517735, gnomAD 0.01%). Disruption of this splice site has been observed in individual(s) with dilated cardiomyopathy (PMID: 22335739, 23418287, 25589632). It has also been observed to segregate with disease in related individuals. This variant is also known as IVS 275+2T>A. ClinVar contains an entry for this variant (Variation ID: 47458). 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)	RCV000184278	SCV000708831	pathogenic	not provided	2017-05-30	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000768876	SCV000900249	pathogenic	Cardiomyopathy	2017-06-12	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000040727	SCV000995191	pathogenic	Primary dilated cardiomyopathy	2018-04-06	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000184278	SCV001714627	pathogenic	not provided	2020-02-25	criteria provided, single submitter	clinical testing	PVS1, PM1, PP1
Revvity Omics, Revvity	RCV000184278	SCV002022469	pathogenic	not provided	2022-02-08	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002354211	SCV002657831	pathogenic	Cardiovascular phenotype	2020-11-02	criteria provided, single submitter	clinical testing	The c.59626+2T>A pathogenic mutation results from a T to A substitution two nucleotides after coding exon 153 in the TTN gene. 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 reported in several dilated cardiomyopathy patients and has been shown to segregate with disease in families (Herman DS et al. N. Engl. J. Med. 2012;366:619-28; Norton N et al. Circ Cardiovasc Genet. 2013;6:144-53; Pugh TJ et al. Genet. Med. 2014;16:601-8). This alteration disrupts the canonical splice site 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 01;49:46-53). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Fulgent Genetics, Fulgent Genetics	RCV002490567	SCV002789403	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	2021-10-02	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV003389235	SCV004101364	pathogenic	Dilated cardiomyopathy 1G	2023-08-14	criteria provided, single submitter	clinical testing	The TTN c.86821+2T>A variant, also referred to as c.79117+2T>A, c.81898+2T>A, or IVS 275+2T>A, results in a substitution at the consensus splice donor site which is predicted to result in splicing defects. This variant affects exon 326 of the meta transcript of titin within the A-band, which is highly expressed in cardiac tissue (PMID: 25589632). In a meta-analysis of TTN truncating variants in patients and controls, variants in this region were associated with a significantly increased risk of developing dilated cardiomyopathy (DCM; odds ratio 49.8) (PMID: 27869827). This variant has been identified in individuals diagnosed with DCM, and has been shown to segregate with disease in multiple families (PMID: 22335739; 23418287; 24503780). This variant is not observed at a significant frequency in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. This variant has been classified as pathogenic by at least three submitters in ClinVar. Based on the available evidence, the c.86821+2T>A variant is classified as pathogenic for dilated cardiomyopathy.
PreventionGenetics, part of Exact Sciences	RCV003982863	SCV004796430	pathogenic	TTN-related condition	2023-12-11	criteria provided, single submitter	clinical testing	The TTN c.86821+2T>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant was reported in the heterozygous and compound heterozygous states in individuals with TTN-related disorders (described as c.81898+2T>A, Herman et al. 2012. PubMed ID: 22335739; described as IVS 275+2T>A, Norton et al. 2013. PubMed ID: 23418287; Martinez-Thompson et al. 2019. PubMed ID: 30681174; Table S2, Goli et al. 2021. PubMed ID: 33874732). This variant is reported in 0.0042% of alleles in individuals of African descent in gnomAD. This variant is located in the canonical splice site within A-band region of the protein in which truncating TTN variants have been found more frequently in dilated cardiomyopathy patients than in controls (Herman et al. 2012. PubMed ID: 22335739). RNAseq studies from heart tissue indicate this exon is commonly included in TTN mRNA transcripts (PSI of 100%); however, this analysis in muscle tissue was not performed (Roberts et al. 2015. PMID: 25589632; https://cardiodb.org/titin/titin_transcripts.php). TTN truncating variants are reported in 1-2% of presumably healthy individuals and occur more frequently in exons with low PSI values, indicating this variant is more likely to be disease causing (Herman et al. 2012. PMID: 22335739; Roberts et al. 2015. PMID: 25589632). In summary, this variant is interpreted as pathogenic for TTN-related disorders.