Submissions for variant NM_001267550.2(TTN):c.31426+1G>C

gnomAD frequency: 0.00001  dbSNP: rs6749719

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000040119	SCV000063810	uncertain significance	not specified	2012-03-14	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The 27694+1G>C variant in TTN has not been previously identified by our laboratory but is liste d in dbSNP (rs6749719) without frequency information. This variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the hig hly conserved splice consensus sequence resulting in an abnormal or absent prote in. Loss-of-function variants in TTN are common in patients with DCM (Herman 201 2), though their role in HCM is unclear. In addition, variants in TTN are also associated with several myopathies (Hackman 2002, Hackman 2008, www.OMIM.org). A lthough this variant is predicted to have a severe impact on the protein, additi onal studies are needed to determine if this is contributes to this patient's cl inical features.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000209261	SCV000189730	uncertain significance	Primary dilated cardiomyopathy	2014-10-08	criteria provided, single submitter	research	This TTN truncating variant (TTNtv) was identified in one individual in this cohort and is located in an exon with intermediate levels of cardiac expression. In the seven cohorts assessed, TTNtv were found in 14% of ambulant DCM, 22% end-stage or familial DCM, and 2% controls. Heterozygous nonsense, frameshift and canonical splice-disrupting variants found in constitutive and other highly utilised exons are highly likely to be pathogenic when identified in individuals with phenotypically confirmed DCM. TTNtv found incidentally in healthy individuals (excluding familial assessment of DCM relatives) are thought to have low penetrance, particularly when identified in exons that are not constitutively expressed in the heart.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000560902	SCV000642967	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2025-01-22	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 117 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 (rs6749719, gnomAD 0.002%). Disruption of this splice site has been observed in individual(s) with TTN-related conditions (PMID: 25589632, 32815318). This variant has been reported in individual(s) with autosomal dominant dilated cardiomyopathy (internal data); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 46849). 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 I band of TTN (PMID: 25589632). Truncating variants in this region have been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875, internal data). Truncating variants in this region have also been identified in individuals affected with autosomal dominant dilated cardiomyopathy and/or cardio-related conditions (PMID: 27869827, 32964742, internal data). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005237460	SCV004804164	likely pathogenic	Autosomal recessive titinopathy	2025-01-16	criteria provided, single submitter	clinical testing	Variant summary: TTN c.27694+1G>C, also known as NM_001267550 c.31426+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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing and loss of TTN function. Loss of function variants in all TTN bands are strongly associated with a spectrum of autosomal recessive titinopathies when exon expression (proportion spliced in, PSI, 1=complete expression) in skeletal muscle is >0.1 (PMID: 36977548, 39198997, 29598826, 32778822, 29691892, 33449170, 36977548, internal data). In contrast, loss of function variants in all TTN bands are only strongly associated with autosomal dominant TTN-related cardiomyopathies if located in exons constitutively expressed (PSI >0.9) in cardiac muscle, excluding extreme C-terminal exons 359-363 (PMID: 25589632, 31216868, 32964742, 34662387, 27869827, Shetty et al., Nat Cardiovasc Res 2024, cardiodb.org, internal data). This variant has a maximum skeletal muscle PSI of 0.956 and a maximum cardiac muscle PSI of 0.740. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5' splicing donor site. At least 1 publication reports this variant was associated with in-frame skipping of exon 114 (exon 117 in NM_001267550), however subsequent protein impacts were unclear (Gohlke_2024). The variant allele was found at a frequency of 2.4e-05 in 1545502 control chromosomes. The variant, c.27694+1G>C, has been reported in the heterozygous state in a few individuals affected with various cardiac and neuromuscular phenotypes, however it was also found in several (apparently) healthy controls (e.g. Roberts_2015, Choi_2018, Rich_2020, Jurgens_2022). One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Gohlke_2024). ClinVar contains an entry for this variant (Variation ID: 46849). Based on the evidence outlined above, the variant was classified as likely pathogenic for autosomal recessive TTN-related conditions.