Submissions for variant NM_001267550.2(TTN):c.36532+2T>G

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005241020	SCV005204873	likely pathogenic	Autosomal recessive titinopathy	2025-01-17	criteria provided, single submitter	clinical testing	Variant summary: TTN c.31484-570T>G is located at a position not widely known to affect splicing. This variant corresponds to c.36532+2T>G in NM_001267550. 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 0.367 and a maximum cardiac muscle PSI of 0.010. 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 allele was found at a frequency of 8.1e-06 in 247880 control chromosomes. To our knowledge, no occurrence of c.31484-570T>G in individuals affected with TTN-related conditions and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 3339637). Based on the evidence outline above, the variant has been classified as Likely Pathogenic for autosomal recessive TTN-related conditions.
Labcorp Genetics (formerly Invitae), Labcorp	RCV005221001	SCV005866815	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-11-07	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 171 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%). This variant has not been reported in the literature in individuals affected with TTN-related conditions. 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.