Submissions for variant NM_001267550.2(TTN):c.67279C>T (p.Arg22427Ter)

dbSNP: rs1200988060

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001059927	SCV001224582	pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-11-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg22427*) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. This variant is present in population databases (no rsID available, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with clinical features of TTN-related conditions (PMID: 31230720, 31660661, 32233023; Invitae). This variant is also known as c.40459C>T (p.Arg13487*). ClinVar contains an entry for this variant (Variation ID: 816836). 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). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV002281145	SCV002569613	pathogenic	not provided	2023-03-15	criteria provided, single submitter	clinical testing	Identified in a patient with DCM in published literature (Stava et al., 2022); Observed in an individual with Wolff-Parkinson-White syndrome and supraventricular tachycardia (Coban-Akdemir et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; 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: 22335739, 31230720, 32233023, 31660661, 35653365)
Revvity Omics, Revvity	RCV002281145	SCV004238389	pathogenic	not provided	2023-05-25	criteria provided, single submitter	clinical testing
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV001007836	SCV001167531	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2J		no assertion criteria provided	research