Submissions for variant NM_001267550.2(TTN):c.93139C>T (p.Arg31047Ter)

gnomAD frequency: 0.00001  dbSNP: rs1416323929

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001995483	SCV002257960	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-03-22	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 1476412). This variant is also known as NM_133437.3:c.66520C>T: p.Arg22174Ter. This premature translational stop signal has been observed in individual(s) with clinical features of autosomal recessive TTN-related conditions (PMID: 31130284). 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. This variant is present in population databases (no rsID available, gnomAD 0.006%). This sequence change creates a premature translational stop signal (p.Arg31047*) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein.
Ambry Genetics	RCV003365618	SCV004053234	likely pathogenic	Cardiovascular phenotype	2023-07-03	criteria provided, single submitter	clinical testing	The p.R21982* variant (also known as c.65944C>T), located in coding exon 166 of the TTN gene, results from a C to T substitution at nucleotide position 65944. This changes the amino acid from an arginine to a stop codon within coding exon 166. 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 alteration has been reported as compound heterozygous with an additional TTN alteration in an individual with muscle weakness and a family history of congenital heart disease (Monies D et al. Am J Hum Genet, 2019 Jun;104:1182-1201). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, 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.
GeneDx	RCV004729007	SCV005333254	likely pathogenic	not provided	2024-03-21	criteria provided, single submitter	clinical testing	Nonsense 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); Reported as p.(R22174*) in a child with muscle weakness who also harbors an intronic +5 splice site variant in the TTN gene; further clinical detail and familial segregation information was not provided (PMID: 31130284); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22335739, 31130284)