Submissions for variant NM_001267550.2(TTN):c.62722C>T (p.Arg20908Ter)

dbSNP: rs543860009

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000424753	SCV000531695	likely pathogenic	not provided	2016-09-26	criteria provided, single submitter	clinical testing	A novel R18340X variant that is likely pathogenic has been identified in the TTN gene. The R18340X variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R18340X nonsense variant in the TTN gene is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R18340X variant is located in the A-band of the titin protein, where the majority of pathogenic truncating variants have been reported. Additionally, other loss of function variants have been reported downstream of the R18340X variant in the Human Gene Mutation Database in association with TTN-related disorder (Stenson et al., 2014). Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Undiagnosed Diseases Network, NIH	RCV000787942	SCV000926963	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2J	2018-12-05	criteria provided, single submitter	clinical testing	A heterozygous c.55018C>T (p.R18340X) pathogenic variant in the TTN gene was detected in this individual. A heterozygous c.95252_95254delCAA (p.T31751del) likely pathogenic variant in the TTN gene was also detected. A heterozygous c.74698A>C (p.K24900Q) variant was also detected and found to be likely benign. The c.55018C>T (p.R18340X) variant is in trans configuration with the c.95252_95254delCAA (p.T31751del) and c.74698A>C (p.K24900Q) variants.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001063221	SCV001228058	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-04-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg20908*) 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 individual(s) with limb-girdle muscular dystrophy and other TTN-related conditions (PMID: 27532257, 27854218). ClinVar contains an entry for this variant (Variation ID: 242424). 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.
Revvity Omics, Revvity	RCV000424753	SCV002021540	likely pathogenic	not provided	2019-07-12	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000424753	SCV002496583	likely pathogenic	not provided	2022-03-01	criteria provided, single submitter	clinical testing	TTN: PVS1:Strong, PM2
Ambry Genetics	RCV003362735	SCV004053273	likely pathogenic	Cardiovascular phenotype	2023-08-09	criteria provided, single submitter	clinical testing	The p.R11843* variant (also known as c.35527C>T), located in coding exon 131 of the TTN gene, results from a C to T substitution at nucleotide position 35527. This changes the amino acid from an arginine to a stop codon within coding exon 131. 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_001267550:c.62722C>T, p.R20908*) has been detected in an individual from a dilated cardiomyopathy genetic testing cohort (Walsh R et al. Genet Med, 2017 Feb;19:192-203), and co-occurred with a second TTN variant in an individual with limb-girdle muscular dystrophy and cardiac findings (Punetha J et al. J Neuromuscul Dis, 2016 May;3:209-225). 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.
Baylor Genetics	RCV004558604	SCV005049482	likely pathogenic	Tibial muscular dystrophy	2024-02-11	criteria provided, single submitter	clinical testing