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

dbSNP: rs794729323

Total submissions: 6

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).
Labcorp Genetics (formerly Invitae), Labcorp	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001386657	SCV001586974	pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-08-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu17437Aspfs*2) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of autosomal dominant TTN-related conditions (Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 202450). 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.
Ambry Genetics	RCV003298243	SCV004004252	pathogenic	Cardiovascular phenotype	2023-03-17	criteria provided, single submitter	clinical testing	The c.25112_25115dupTTGA pathogenic mutation, located in coding exon 101 of the TTN gene, results from a duplication of TTGA at nucleotide position 25112, causing a translational frameshift with a predicted alternate stop codon (p.E8372Dfs*2). This exon is located in the A-band region of the N2-B isoform of the titin protein and is constitutively expressed in TTN transcripts (percent spliced in or PSI 100%). This alteration (also noted as NM_001267550.1: c.52307_52310dupTTGA (E17437Dfs*2)) has been reported in association with dilated cardiomyopathy (DCM) (Jansen M et al. Circ Genom Precis Med, 2019 May;12:e002436; Augusto JB et al. Eur Heart J Cardiovasc Imaging, 2020 Mar;21:326-336; Nguyen TV et al. Circ J, 2021 Aug;85:1469-1478). In addition, this variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. While truncating variants in TTN are present in 1-3% of the general population, truncating variants in the A-band are the most common cause of dilated cardiomyopathy (DCM) (Herman DS et al. N. Engl. J. Med., 2012 Feb;366:619-28; Roberts AM et al. Sci Transl Med, 2015 Jan;7:270ra6). TTN truncating variants encoded in constitutive exons (PSI >90%) have been found to be significantly associated with DCM regardless of their position in titin (Schafer S et al. Nat. Genet., 2017 01;49:46-53). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000184311	SCV000924986	likely pathogenic	not provided	2016-07-12	no assertion criteria provided	provider interpretation
KTest Genetics, KTest	RCV000458641	SCV001499992	pathogenic	Dilated cardiomyopathy 1G		no assertion criteria provided	clinical testing