Submissions for variant NM_001267550.2(TTN):c.58270G>T (p.Glu19424Ter)

dbSNP: rs72646837

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000184244	SCV000236866	pathogenic	not provided	2017-01-23	criteria provided, single submitter	clinical testing	p.Glu17783Stop (GAA>TAA): c.53347 G>T in exon 247 of the TTN gene (NM_001256850.1). The Glu17783Stop mutation in the TTN gene has been reported previously in association with DCM (Herman D et al., 2012). Glu17783Stop is predicted to cause loss of normal protein function either due to production of an abnormal, prematurely truncated protein, or by absence of protein product due to nonsense mediated mRNA decay. Other truncating TTN variants have been reported in approximately 3% of control alleles (Herman D et al., 2012). However, Glu17783Stop is located in the A-band region of titin, where the majority of truncating mutations associated with DCM have been reported (Herman D et al., 2012). Furthermore, Glu17783Stop was not observed in approximately 6000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, Glu17783Stop in the TTN gene is interpreted as a disease-causing mutation. The variant is found in DCM panel(s).
Invitae	RCV001852385	SCV002173528	pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-09-21	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu19424*) 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 premature translational stop signal has been observed in individuals with dilated cardiomyopathy (PMID: 22335739; Invitae). For these reasons, this variant has been classified as Pathogenic. 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). ClinVar contains an entry for this variant (Variation ID: 202395). This variant is also known as c.53347G>T (p.Glu17783X).