Submissions for variant NM_001267550.2(TTN):c.56648-1G>A

gnomAD frequency: 0.00001  dbSNP: rs769912484

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000824892	SCV000965809	likely pathogenic	Early-onset myopathy with fatal cardiomyopathy	2015-01-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001248302	SCV001421775	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-10-28	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 290 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 (rs769912484, gnomAD 0.005%). Disruption of this splice site has been observed in individual(s) with autosomal recessive centronuclear myopathy (PMID: 34440373). ClinVar contains an entry for this variant (Variation ID: 666351). 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	RCV002279552	SCV002567562	likely pathogenic	not provided	2022-02-01	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; Located in the A-band region of the TTN gene, where the majority of truncating pathogenic variants associated with dilated cardiomyopathy have been reported (Herman et al., 2012); This variant is associated with the following publications: (PMID: 34440373)
Cardiogenetics and Myogenetics Molecular and Cellular Functional Unit, Aphp Sorbonne University-Hopital Pitie Salpetriere	RCV004764944	SCV005375126	uncertain significance	Dilated cardiomyopathy 1G	2024-01-06	no assertion criteria provided	clinical testing