Submissions for variant NM_001267550.2(TTN):c.12587C>A (p.Ser4196Ter)

gnomAD frequency: 0.00010  dbSNP: rs370912401

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041096	SCV000064787	uncertain significance	not specified	2012-05-23	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The Ser3958X va riant in TTN has been identified in 1/6588 European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington .edu/EVS). This frequency is not high enough to rule out a disease causing role as this individual could have been presymptomatic. This nonsense variant leads t o a premature termination codon at position 3958, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the TTN gene is strongly associated with DCM (Herman 2012). Although this data supports that the Ser3958X variant may be pathogenic, this variant has not been detected in isola tion and thus, additional studies are needed to fully assess its clinical signif icance.
Invitae	RCV000233246	SCV000286437	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2022-11-01	criteria provided, single submitter	clinical testing	This premature translational stop signal has been observed in individual(s) with clinical features of TTN-related conditions (PMID: 24503780, 27532257, 30535219). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant is located in the I band of TTN (PMID: 25589632). Truncating variants in this region have been shown to be highly prevalent in the general population and unaffected individuals (PMID: 26701604, 22335739). However, truncating variants in this region have also been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875). ClinVar contains an entry for this variant (Variation ID: 47827). This variant is present in population databases (rs370912401, gnomAD 0.004%). This sequence change creates a premature translational stop signal (p.Ser4196*) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein.
GeneDx	RCV000766916	SCV000680711	likely pathogenic	not provided	2023-08-30	criteria provided, single submitter	clinical testing	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); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27532257, 24503780, 30535219, 34495297, 31983221, 36264615, 27625338, 27869827)
Ambry Genetics	RCV002453335	SCV002617443	likely pathogenic	Cardiovascular phenotype	2022-10-11	criteria provided, single submitter	clinical testing	The p.S3833* variant (also known as c.11498C>A), located in coding exon 44 of the TTN gene, results from a C to A substitution at nucleotide position 11498. This changes the amino acid from a serine to a stop codon within coding exon 44. 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 (referred to as c.11873C>A p.Ser3958X and c.12587C>A p.S4196X) has been reported in an in individual with dilated cardiomyopathy (DCM) and in an individual referred for DCM genetic testing; however, these patient reports may overlap (Pugh TJ et al. Genet Med, 2014 Aug;16:601-8; Walsh R et al. Genet Med, 2017 02;19:192-203). 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 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.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000766916	SCV001930698	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000766916	SCV001958780	likely pathogenic	not provided		no assertion criteria provided	clinical testing