Submissions for variant NM_001267550.2(TTN):c.34612+1G>A

gnomAD frequency: 0.00001  dbSNP: rs577363824

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000473977	SCV000542748	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 150 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 (rs577363824, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with TTN-related conditions. ClinVar contains an entry for this variant (Variation ID: 404922). 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, Invitae 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, Invitae 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.
Genetic Services Laboratory, University of Chicago	RCV000502600	SCV000597697	pathogenic	not provided	2016-07-21	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV001256858	SCV001433348	likely pathogenic	Dilated cardiomyopathy 1A	2020-03-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001824786	SCV002074149	uncertain significance	not specified	2022-01-08	criteria provided, single submitter	clinical testing	Variant summary: TTN c.30709+1G>A (also known as NM_001267550.2:c.34612+1G>A) alters a conserved nucleotide 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 the canonical 5' splicing donor site located at intron 145. However, these predictions have yet to be confirmed by functional studies. Furthermore, the exon predicted to be impacted by this alteration is not a constitutively expressed exon (low PSI score) and therefore the clinical impact of this splicing alteration is unknown. The variant allele was found at a frequency of 1.6e-05 in 185860 control chromosomes. c.30709+1G>A has not been reported in the literature in individuals affected with Limb-Girdle Muscular Dystrophy, Type 2J/Cardiomyopathy. However, it has been reported in at-least two controls individuals of European ancestery in the UK Biobank (example, Choi_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Limb-Girdle Muscular Dystrophy, Type 2J/Cardiomyopathy. 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. Based on the evidence outlined above, the variant was classified as uncertain significance.