Submissions for variant NM_001267550.2(TTN):c.59351_59352del (p.Pro19784fs)

dbSNP: rs886039027

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000245184	SCV000319714	likely pathogenic	Cardiovascular phenotype	2022-11-17	criteria provided, single submitter	clinical testing	The c.32156_32157delCT variant, located in coding exon 128 of the TTN gene, results from a deletion of two nucleotides at nucleotide positions 32156 to 32157, causing a translational frameshift with a predicted alternate stop codon (p.P10719Rfs*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, referred to as c.51647_51648del (p.P17216Rfs*5), has been detected in an individual reported to have dilated cardiomyopathy (van Lint FHM et al. Neth Heart J. 2019 Jun;27(6):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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000704831	SCV000833801	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2025-01-07	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Pro19784Argfs*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 (no rsID available, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with cardiomyopathy and/or peripartum cardiomyopathy (PMID: 30847666, 33106378; internal data). This variant is also known as c.51647_51648delCT p.(Pro17216Argfs*5). ClinVar contains an entry for this variant (Variation ID: 264060). 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.
Eurofins Ntd Llc (ga)	RCV000734246	SCV000862370	likely pathogenic	not provided	2018-07-12	criteria provided, single submitter	clinical testing
GeneDx	RCV000734246	SCV002599786	pathogenic	not provided	2023-03-09	criteria provided, single submitter	clinical testing	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 the A-band region of TTN in which the majority of loss of function variants have been associated with autosomal dominant titinopathies (Herman et al., 2012); This variant is associated with the following publications: (PMID: 30847666, 22335739, 33106378)
CeGaT Center for Human Genetics Tuebingen	RCV000734246	SCV003916186	likely pathogenic	not provided	2024-08-01	criteria provided, single submitter	clinical testing	TTN: PVS1:Strong, PM2:Supporting, PS4:Supporting
Institute of Immunology and Genetics Kaiserslautern	RCV004771470	SCV005382126	pathogenic	Dilated cardiomyopathy 1G	2022-08-04	criteria provided, single submitter	clinical testing	ACMG Criteria: PVS1, PM2, PP5; Variant was found in heterozygous state.
Clinical Genetics, Academic Medical Center	RCV000734246	SCV001923682	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000734246	SCV001963363	likely pathogenic	not provided		no assertion criteria provided	clinical testing