Submissions for variant NM_001267550.2(TTN):c.52406-2A>C

gnomAD frequency: 0.00002  dbSNP: rs753798236

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000642796	SCV000764483	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-12-12	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 274 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 (rs753798236, gnomAD 0.005%). 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: 535037). 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.
Revvity Omics, Revvity	RCV001784218	SCV002021512	likely pathogenic	not provided	2020-09-18	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV001784218	SCV002502877	likely pathogenic	not provided	2022-02-17	criteria provided, single submitter	clinical testing
GeneDx	RCV001784218	SCV002567434	likely pathogenic	not provided	2022-07-21	criteria provided, single submitter	clinical testing	Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV002458070	SCV002738715	uncertain significance	Cardiovascular phenotype	2023-09-11	criteria provided, single submitter	clinical testing	The c.25211-2A>C intronic variant results from an A to C substitution two nucleotides upstream from coding exon 102 in the TTN gene. Exon 102 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 acceptor site and will result in the creation or strengthening of a novel splice acceptor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNA decay. The exact functional effect of the missing amino acids is unknown. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.