Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Laboratory for Molecular Medicine, |
RCV000040594 | SCV000064285 | likely pathogenic | Primary dilated cardiomyopathy | 2013-01-18 | criteria provided, single submitter | clinical testing | The Glu22047fs variant in TTN has not been reported in the literature but has be en identified in one Caucasian individual with DCM previously tested by our labo ratory. This frameshift variant is predicted to alter the protein?s amino acid s equence beginning at position 22047 and lead to a premature termination codon 9 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Truncating variants in TTN are strongly associated with DCM (Herman 2012). In summary, this variant is likely to be pathogenic, though segre gation studies and functional analyses are required to establish this with certa inty. |
Labcorp Genetics |
RCV000692633 | SCV000820466 | likely pathogenic | Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J | 2022-03-19 | 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: 47324). This variant is also known as p.Glu22047AspfsX9. This premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy (PMID: 24503780). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu24615Aspfs*9) 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 | RCV002336146 | SCV002636164 | pathogenic | Cardiovascular phenotype | 2022-09-13 | criteria provided, single submitter | clinical testing | The c.46650delA pathogenic mutation, located in coding exon 153 of the TTN gene, results from a deletion of one nucleotide at nucleotide position 46650, causing a translational frameshift with a predicted alternate stop codon (p.E15550Dfs*9). 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 c.66141delA, p.Glu22047Aspfs*9) has been reported in an individual with dilated cardiomyopathy (Pugh TJ et al. Genet Med, 2014 Aug;16:601-8). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV003235002 | SCV003934134 | pathogenic | Primary familial dilated cardiomyopathy | 2023-05-23 | criteria provided, single submitter | clinical testing | Variant summary: TTN c.66141delA (p.Glu22047AspfsX9) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 247880 control chromosomes. c.66141delA has been reported in the literature in at least one individual affected with Dilated Cardiomyopathy (Pugh_2014). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 24503780). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as pathogenic/likely pathogenic. 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). Based on the evidence outlined above, the variant was classified as pathogenic. |