Submissions for variant NM_001267550.2(TTN):c.45316_45320dup (p.Arg15108fs)

dbSNP: rs794729390

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000184407	SCV000237032	pathogenic	not provided	2023-04-10	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign in a peer-reviewed publication to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); 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 a region of TTN within the I-band in which the majority of loss of function variants are significantly associated with autosomal dominant titinopathies (Deo et al., 2016; Schafer et al., 2017); This variant is associated with the following publications: (PMID: 27625338, 27869827)
Ambry Genetics	RCV000620246	SCV000735922	likely pathogenic	Cardiovascular phenotype	2024-07-03	criteria provided, single submitter	clinical testing	The c.18121_18125dupAGCTC variant, located in coding exon 72 of the TTN gene, results from a duplication of AGCTC at nucleotide position 18121, causing a translational frameshift with a predicted alternate stop codon (p.R6043Afs*71). This exon is located in the I-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 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). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001241598	SCV001414626	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2025-01-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg15108Alafs*71) 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 variant has not been observed in the literature in individuals with autosomal recessive TTN-related conditions. This variant has been reported in individual(s) with clinical features of dilated cardiomyopathy (PMID: 32815318); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 202537). This variant is located in the I band of TTN (PMID: 25589632). Truncating variants in this region have been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875, internal data). Truncating variants in this region have also been identified in individuals affected with autosomal dominant dilated cardiomyopathy and/or cardio-related conditions (PMID: 27869827, 32964742, internal data). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Baylor Genetics	RCV003147383	SCV003835367	likely pathogenic	Left ventricular noncompaction 2	2022-08-22	criteria provided, single submitter	clinical testing