Submissions for variant NM_001267550.2(TTN):c.51739+1G>C

dbSNP: rs727504799

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000156125	SCV000205839	likely pathogenic	Primary dilated cardiomyopathy	2013-10-04	criteria provided, single submitter	clinical testing	The 44035+1G>A variant in TTN has not been reported in individuals with cardiomy opathy or in large population studies. This variant occurs in the invariant regi on (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Alternative splicing and othe r truncating variants in TTN are strongly associated with DCM (Herman 2012). In summary, this variant is likely pathogenic, though additional studies are requir ed to fully establish its clinical significance.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770016	SCV000901442	pathogenic	Cardiomyopathy	2017-10-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002426753	SCV002731582	uncertain significance	Cardiovascular phenotype	2021-06-03	criteria provided, single submitter	clinical testing	The c.24544+1G>C intronic variant results from a G to C substitution one nucleotide after coding exon 99 of the TTN gene. Coding exon 99 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 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. 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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002516148	SCV003195664	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-06-25	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 272 of the TTN gene. It is expected to disrupt RNA splicing and likely results in a truncated or disrupted TTN protein. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of TTN-related conditions (PMID: 36138163). ClinVar contains an entry for this variant (Variation ID: 179336). 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). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneDx	RCV003229813	SCV003927527	likely pathogenic	not provided	2023-05-26	criteria provided, single submitter	clinical testing	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); Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 22335739)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004786413	SCV005400575	likely pathogenic	Dilated cardiomyopathy 1G	2020-06-11	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as likely pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0104 - Dominant Negative is a mechanism of disease for this gene. (N) 0108 - This gene is known to be associated with both recessive and dominant disease. (N) 0112 - Variants in this gene are known to have reduced penetrance (PMID: 25589632; PMID: 28045975). (N) 0211 - Canonical splice site variant located in intron 100 of 190, without proven consequence on splicing (no functional evidence available). (P) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (P) 0600 - Variant is located in an annotated domain or motif (PSI = 1, A band; PMID: 25589632). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0803 - Low previous evidence of pathogenicity. This variant has been reported likely pathogenic in two unrelated patients with cardiomyopathy (ClinVar). (P) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign