Submissions for variant NM_001267550.2(TTN):c.89197+1G>C

gnomAD frequency: 0.00003  dbSNP: rs1131691873

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000493724	SCV000583040	likely pathogenic	not provided	2022-12-22	criteria provided, single submitter	clinical testing	Identified in at least one patient with early-onset atrial fibrillation (AF) in published literature (Choi et al., 2018; Yoneda et al., 2021); Not observed at 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 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, 34495297, 30535219)
Ambry Genetics	RCV000617501	SCV000735514	likely pathogenic	Cardiovascular phenotype	2022-01-12	criteria provided, single submitter	clinical testing	The c.62002+1G>C intronic variant results from a G to C substitution one nucleotide after coding exon 160 of the TTN gene. Exon 160 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 is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. 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). As such, this alteration is classified as likely pathogenic.
Invitae	RCV001206208	SCV001377505	pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-08-16	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 430269). Disruption of this splice site has been observed in individuals with dilated cardiomyopathy and/or early-onset atrial fibrillation (PMID: 30535219; Invitae). This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change affects a donor splice site in intron 333 of the TTN gene. It is expected to disrupt RNA splicing and likely results in a truncated or disrupted TTN protein.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001280576	SCV001467779	likely pathogenic	Primary familial dilated cardiomyopathy	2020-12-14	criteria provided, single submitter	clinical testing	Variant summary: TTN c.81493+1G>C 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: Four predict the variant abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 230186 control chromosomes (gnomAD). c.81493+1G>C has been reported in the literature in one individual affected with Dilated Cardiomyopathy (Choi_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000493724	SCV004226728	likely pathogenic	not provided	2023-01-27	criteria provided, single submitter	clinical testing	PP3, PS4_supporting, PVS1_strong