Submissions for variant NM_001267550.2(TTN):c.50083C>T (p.Arg16695Ter)

dbSNP: rs751502842

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000184224	SCV000236846	pathogenic	not provided	2015-11-03	criteria provided, single submitter	clinical testing	The Arg15054Stop variant in the TTN gene has not been reported previously as a disease-causing mutation nor as a benign polymorphism, to our knowledge. Arg15054Stop is predicted to cause loss of normal protein function either due to production of an abnormal, prematurely truncated protein, or by absence of protein product due to nonsense mediated mRNA decay. Arg15054Stop is located in the A-band region of titin, where the majority of truncating mutations associated with DCM have been reported (Herman D et al., 2012).
Invitae	RCV000555213	SCV000642433	pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg16695*) 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 premature translational stop signal has been observed in individuals with dilated cardiomyopathy (PMID: 25163546; Invitae). ClinVar contains an entry for this variant (Variation ID: 202377). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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). For these reasons, this variant has been classified as Pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170835	SCV001333455	pathogenic	Cardiomyopathy	2020-01-03	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001196220	SCV001366770	pathogenic	Tibial muscular dystrophy	2019-05-21	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP4,PP5.
Ambry Genetics	RCV003362717	SCV004053233	likely pathogenic	Cardiovascular phenotype	2023-07-12	criteria provided, single submitter	clinical testing	The p.R7630* variant (also known as c.22888C>T), located in coding exon 93 of the TTN gene, results from a C to T substitution at nucleotide position 22888. This changes the amino acid from an arginine to a stop codon within coding exon 93. 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 NM_133437:c.23464C>T p.R7822X) has been detected in a dilated cardiomyopathy cohort (Haas J et al. Eur Heart J, 2015 May;36:1123-35a). 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.
Clinical Genetics, Academic Medical Center	RCV000184224	SCV001923657	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000184224	SCV001962841	likely pathogenic	not provided		no assertion criteria provided	clinical testing