Submissions for variant NM_001267550.2(TTN):c.67349-2A>C

gnomAD frequency: 0.00001  dbSNP: rs753948675

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001047479	SCV001211441	pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2022-10-31	criteria provided, single submitter	clinical testing	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). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 242425). Disruption of this splice site has been observed in individual(s) with centronuclear myopathy (PMID: 27159402, 27854218). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs753948675, gnomAD 0.0009%). This sequence change affects an acceptor splice site in intron 318 of the TTN gene. It is expected to disrupt RNA splicing and likely results in a truncated or disrupted TTN protein. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001571802	SCV001796336	likely pathogenic	not provided	2023-06-07	criteria provided, single submitter	clinical testing	Reported as c.59645-2A>C in an individual with sudden cardiac death and past history of atherosclerotic cardiovascular disease (Khera et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); 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; Located in the A-band region of TTN in which the majority of loss of function variants have been associated with autosomal dominant titinopathies (Herman et al., 2012); This variant is associated with the following publications: (PMID: 27854218, 32597815, 34315225, 22335739, 31727422, 31954878, 27159402)
AiLife Diagnostics, AiLife Diagnostics	RCV001571802	SCV002501445	pathogenic	not provided	2021-09-20	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002494674	SCV002788427	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J; Tibial muscular dystrophy; Myopathy, myofibrillar, 9, with early respiratory failure; Early-onset myopathy with fatal cardiomyopathy; Hypertrophic cardiomyopathy 9	2021-11-03	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003150141	SCV003837981	likely pathogenic	Cardiomyopathy	2021-11-30	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017533	SCV004848188	likely pathogenic	Primary dilated cardiomyopathy	2018-07-25	criteria provided, single submitter	clinical testing	The c.59645-2A>C variant in TTN has been reported in compound heterozygous state in 1 individual with congenital muscular dystrophy and DCM (reported as c.67349-2A>C, O'Grady 2016). It has also been identified in 1/109468 of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs753948675) and has been reported in ClinVar (Variation ID: 424832). This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Truncating variants in TTN are strongly associated with DCM if they impact the exons encoding for the A-band (Herman 2012, Pugh 2014) and/or are located in an exon that is highly expressed in the heart (Roberts 2015). The c.59645-2A>C variant is located in A-band adjacent to the highly expressed exon 267. In summary, although additional studies are required to fully establish its clinical significance, the c.59645-2A>C variant is likely pathogenic. ACMG/AMP Criteria applied: PM2; PM3; PVS1_Moderate.