ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.52307_52310dup (p.Glu17437delinsAspTer) (rs794729323)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000184311 SCV000236936 pathogenic not provided 2014-06-16 criteria provided, single submitter clinical testing p.Glu15796AspfsX2 (E15796DfsX2) : c.47384_47387dupTTGA in exon 224 of the TTN gene (NM_001256850.1). The normal sequence with the bases that are duplicated in braces is: CTGA{TTGA}AGGA. Although the c.47384_47387dupTTGA mutation in the TTN gene has not been reported to our knowledge, this mutation causes a shift in reading frame starting at codon Glutamic acid 15796, changing it to an Aspartic acid, and creating a premature stop codon at position 2 of the new reading frame, denoted p.Glu15796AspfsX2. This mutation is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other truncating TTN variants have been reported in approximately 3% of control alleles (Herman D et al., 2012). However, c.47384_47387dupTTGA 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). Therefore, the presence of this mutation indicates that this individual is at increased risk to develop a cardiomyopathy. The variant is found in TTN panel(s).
Invitae RCV000458641 SCV000542594 pathogenic Dilated cardiomyopathy 1G 2016-08-30 criteria provided, single submitter clinical testing This sequence change inserts 4 nucleotides in exon 274 of the TTN mRNA (c.52307_52310dupTTGA), causing a frameshift at codon 17437. This creates a premature translational stop signal (p.Glu17437Aspfs*2). While this is not anticipated to result in nonsense mediated decay, it is expected to result in a truncated TTN protein. This variant is found in the A-band of this gene. While this particular variant has not been reported in the literature, truncating variants in the A-band of TTN are significantly overrepresented in patients with dilated cardiomyopathy and are considered to be likely pathogenic for the disease (PMID: 25589632). ClinVar contains an entry for this variant (Variation ID: 202450). For these reasons, this variant has been classified as Pathogenic.
Invitae RCV001386657 SCV001586974 pathogenic Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2016-08-30 criteria provided, single submitter clinical testing This sequence change inserts 4 nucleotides in exon 274 of the TTN mRNA (c.52307_52310dupTTGA), causing a frameshift at codon 17437. This creates a premature translational stop signal (p.Glu17437Aspfs*2). While this is not anticipated to result in nonsense mediated decay, it is expected to result in a truncated TTN protein. This variant is found in the A-band of this gene. While this particular variant has not been reported in the literature, truncating variants in the A-band of TTN are significantly overrepresented in patients with dilated cardiomyopathy and are considered to be likely pathogenic for the disease (PMID: 25589632). ClinVar contains an entry for this variant (Variation ID: 202450). For these reasons, this variant has been classified as Pathogenic.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000184311 SCV000924986 likely pathogenic not provided 2016-07-12 no assertion criteria provided provider interpretation

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