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	2025-04-14	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; This variant is associated with the following publications: (PMID: 34495297, 30535219, 22335739, 32778822)
Ambry Genetics	RCV000617501	SCV000735514	likely pathogenic	Cardiovascular phenotype	2025-01-03	criteria provided, single submitter	clinical testing	The c.62002+1G>C intronic variant results from a G to C substitution one nucleotide after exon 161 (coding exon 160) of the TTN gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on data from gnomAD, the C allele has an overall frequency of 0.003% (1/31408) total alleles studied. The highest observed frequency was 0.007% (1/15434) of European (non-Finnish) alleles. This nucleotide position is highly conserved in available vertebrate species. Exon 161 (coding 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%). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001206208	SCV001377505	pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2025-01-27	criteria provided, single submitter	clinical testing	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. This variant is present in population databases (no rsID available, gnomAD 0.007%). Disruption of this splice site has been observed in individuals with dilated cardiomyopathy and/or early-onset atrial fibrillation (PMID: 30535219; internal data). ClinVar contains an entry for this variant (Variation ID: 430269). 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.
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