Submissions for variant NM_001267550.2(TTN):c.41793C>A (p.Tyr13931Ter)

dbSNP: rs794729380

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000184386	SCV000237011	likely pathogenic	not provided	2024-01-23	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); 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 (PMID: 27625338, 27869827); This variant is associated with the following publications: (PMID: 27625338, 27869827)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001175440	SCV001338998	uncertain significance	not specified	2020-03-23	criteria provided, single submitter	clinical testing	Variant summary: TTN c.34089C>A (p.Tyr11363X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay. The variant was absent in 222036 control chromosomes. To our knowledge, no occurrence of c.34089C>A in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Frameshift and other truncating variants in TTN are strongly associated with DCM if they are located in the exons encoding for the A-band (PMID: 22335739, PMID: 24503780) and/or are located in an exon that is highly expressed in the heart (PMID: 25589632). This variant is located in the I-band region of the protein, but is indicated to be in an exon that is highly expressed in the heart. However, other nearby variants have been classified as VUS in ClinVar. Based on the evidence outlined above, the variant was classified as VUS.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001852396	SCV002131080	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-11-26	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr13931*) 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 variant has not been observed in the literature in individuals with autosomal recessive TTN-related conditions. This variant has been reported in individual(s) with autosomal dominant dilated cardiomyopathy (internal data); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 202517). This variant is located in the I band of TTN (PMID: 25589632). Truncating variants in this region have been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875, internal data). Truncating variants in this region have also been identified in individuals affected with autosomal dominant dilated cardiomyopathy and/or cardio-related conditions (PMID: 27869827, 32964742, internal data). 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.
Ambry Genetics	RCV004678630	SCV005173503	likely pathogenic	Cardiovascular phenotype	2024-04-25	criteria provided, single submitter	clinical testing	The p.Y4866* variant (also known as c.14598C>A), located in coding exon 54 of the TTN gene, results from a C to A substitution at nucleotide position 14598. This changes the amino acid from a tyrosine to a stop codon within coding exon 54. 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 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). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.