Submissions for variant NM_001267550.2(TTN):c.94103_94107del (p.Ile31368fs)

dbSNP: rs769488730

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000184360	SCV000236985	pathogenic	not provided	2021-10-27	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Frameshift 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 titin, where the majority of truncating pathogenic variants associated with DCM have been reported (Herman et al., 2012); This variant is associated with the following publications: (PMID: 22335739)
Invitae	RCV001246299	SCV001419642	pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ile31368Serfs*34) 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 (rs769488730, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with dilated cardiomyopathy and/or peripartum cardiomyopathy (PMID: 22335739, 35653365, 36264615; Invitae). This variant is also known as c.89180_89184delAAATT. ClinVar contains an entry for this variant (Variation ID: 202493). 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	RCV002362950	SCV002663544	pathogenic	Cardiovascular phenotype	2023-07-25	criteria provided, single submitter	clinical testing	The c.66908_66912delTTAAA pathogenic mutation, located in coding exon 166 of the TTN gene, results from a deletion of 5 nucleotides at nucleotide positions 66908 to 66912, causing a translational frameshift with a predicted alternate stop codon (p.I22303Sfs*34). 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 has been reported, as c.89180_89184delTTAAA, in a subject with dilated cardiomyopathy (DCM) (Herman DS et al. N. Engl. J. Med., 2012 Feb;366:619-28). 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000184360	SCV004226726	likely pathogenic	not provided	2022-04-07	criteria provided, single submitter	clinical testing	PM2_supporting, PVS1
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV001254759	SCV001430852	likely pathogenic	Mitral valve prolapse	2019-01-03	no assertion criteria provided	research	This variant has been identified as part of our research program. Refer to the 'condition' field for the phenotype of the proband identified with this variant. For further information please feel free to contact us.