Submissions for variant NM_001267550.2(TTN):c.59201_59202del (p.Pro19734fs)

dbSNP: rs752948913

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000479171	SCV000567027	likely pathogenic	not provided	2022-01-11	criteria provided, single submitter	clinical testing	Identified by a large next-generation sequencing panel in an individual with dilated cardiomyopathy who harbored another TTN variant, the phase of which was unknown (van Lint et al., 2019); Identified in a patient with peripartum cardiomyopathy, but familial segregation information and additional clinical information was not included (Goli et al., 2021); 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; Not observed at significant frequency in large population cohorts (gnomAD); Located in the A-band region of titin, where the majority of truncating variants associated with DCM have been reported (Herman D et al., 2012).; This variant is associated with the following publications: (PMID: 33874732, 30847666)
Blueprint Genetics	RCV000479171	SCV000927260	likely pathogenic	not provided	2017-05-11	criteria provided, single submitter	clinical testing
Invitae	RCV000823812	SCV000964682	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-09-15	criteria provided, single submitter	clinical testing	This premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy and/or peripartum cardiomyopathy (PMID: 30847666, 33874732). This sequence change creates a premature translational stop signal (p.Pro19734Argfs*5) 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 (rs752948913, gnomAD 0.0009%). This variant is also known as c.51497_51498del. ClinVar contains an entry for this variant (Variation ID: 419310). 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). 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.
Ambry Genetics	RCV002323821	SCV002610837	likely pathogenic	Cardiovascular phenotype	2021-06-28	criteria provided, single submitter	clinical testing	The c.32006_32007delCT variant, located in coding exon 127 of the TTN gene, results from a deletion of two nucleotides at nucleotide positions 32006 to 32007, causing a translational frameshift with a predicted alternate stop codon (p.P10669Rfs*5). 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 variant was reported (as NM_133378.4 c.51497_51498del, p.Pro17166Argfs*5) in a cardiomyopathy genetic testing cohort; however, clinical details were limited, and an additional cardiac variant was detected (van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). 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). As such, this alteration is classified as likely pathogenic.