Submissions for variant NM_001267550.2(TTN):c.54418C>T (p.Arg18140Ter)

gnomAD frequency: 0.00001  dbSNP: rs747236787

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000703169	SCV000832056	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2022-09-12	criteria provided, single submitter	clinical testing	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 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). ClinVar contains an entry for this variant (Variation ID: 579797). This variant has not been reported in the literature in individuals affected with TTN-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Arg18140*) 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	RCV001560483	SCV001782903	likely pathogenic	not provided	2023-04-02	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 (Herman et al., 2012); Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22335739)
Ambry Genetics	RCV002424697	SCV002741459	likely pathogenic	Cardiovascular phenotype	2022-05-27	criteria provided, single submitter	clinical testing	The p.R9075* variant (also known as c.27223C>T), located in coding exon 109 of the TTN gene, results from a C to T substitution at nucleotide position 27223. This changes the amino acid from an arginine to a stop codon within coding exon 109. 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 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.
New York Genome Center	RCV003336156	SCV004046515	likely pathogenic	Dilated cardiomyopathy 1G; Hypertrophic cardiomyopathy 9	2023-03-09	criteria provided, single submitter	clinical testing	The c.54418C>T variant identified in TTN has not been reported previously in individuals with titinopathies; it has been reported in ClinVar as Likely pathogenic by three submitters [ClinVar ID: 579797]. The c.54418C>T variant is observed in 2 alleles (~0.0009% minor allele frequency with 0 homozygote) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases. The c.54418C>T variant is located in exon 282 (A-band) of this 363-exon gene, is predicted to incorporate a premature termination codon (p.(Arg18140Ter), and is expected to result in loss-of-function either through protein truncation or nonsense-mediated mRNA decay. Based on available evidence, this c.54418C>T p.(Arg18140Ter) variant identified in TTN is classified as Likely Pathogenic.