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

dbSNP: rs752948913

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000479171	SCV000567027	pathogenic	not provided	2024-06-24	criteria provided, single submitter	clinical testing	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 TTN in which the majority of loss of function variants have been associated with autosomal dominant titinopathies (PMID: 22335739); Not observed at significant frequency in large population cohorts (gnomAD); Identified in patients with DCM or peripartum cardiomyopathy in published literature and referred for genetic testing at GeneDx; at least one patient harbored an additional cardiogenetic variant (PMID: 30847666, 33874732); This variant is associated with the following publications: (PMID: 35177841, 33874732, 22335739, 30847666, 31691645, 36264615)
Blueprint Genetics	RCV000479171	SCV000927260	likely pathogenic	not provided	2017-05-11	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	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	2023-11-02	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 (also referred to as as NM_133378.4:c.51497_51498del, p.Pro17166Argfs*5 and NM_001267550.1:c.59201_59202delCT, p.Pro19734Argfs*5) has been detected in a cardiomyopathy genetic testing cohort and in a peripartum cardiomyopathy cohort (van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). 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 majority of available evidence to date, this variant is likely to be pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004764928	SCV005399936	likely pathogenic	Dilated cardiomyopathy 1G	2020-10-19	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0104 - Dominant Negative is a mechanism of disease for this gene. (N) 0108 - This gene is known to be associated with both recessive and dominant disease. (N) 0112 - Variants in this gene are known to have reduced penetrance (Franaszczyk, M. et al. (2017)). (N) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein. (exon 128 of 191). (P) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (P) 0507 - Identified variant type is not compatible with in-silico predictions of pathogenicity. (N) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants. TTN A-band, PSI score= 1 (Roberts, A. et al. (2015)). (N) 0703 - Comparable variants have moderate previous evidence for pathogenicity. (ClinVar, Decipher). (P) 0802 - Moderate previous evidence of pathogenicity in unrelated individuals. Reported likely pathogenic in one DCM patient (van Lint, F. et al. (2019)) and listed as likely pathogenic in three individuals (ClinVar). (P) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Segregation information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Cardiogenetics and Myogenetics Molecular and Cellular Functional Unit, Aphp Sorbonne University-Hopital Pitie Salpetriere	RCV004764928	SCV005375202	likely pathogenic	Dilated cardiomyopathy 1G	2024-01-06	no assertion criteria provided	clinical testing