Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000482113 | SCV000567334 | pathogenic | not provided | 2021-01-26 | criteria provided, single submitter | clinical testing | Has not been previously published as pathogenic or benign to our knowledge; Not observed in large population cohorts (Lek et al., 2016); 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 |
Labcorp Genetics |
RCV001851164 | SCV002295938 | likely pathogenic | Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J | 2020-11-05 | 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). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in individual(s) with dilated cardiomyopathy (PMID: 24119082). This variant is also known as c.52408C>T (p.R17470X). ClinVar contains an entry for this variant (Variation ID: 419495). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln26535*) 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 | RCV002341131 | SCV002645018 | likely pathogenic | Cardiovascular phenotype | 2022-02-25 | criteria provided, single submitter | clinical testing | The p.Q17470* variant (also known as c.52408C>T), located in coding exon 153 of the TTN gene, results from a C to T substitution at nucleotide position 52408. This changes the amino acid from a glutamine to a stop codon within coding exon 153. 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. |
Cardiogenetics and Myogenetics Molecular and Cellular Functional Unit, |
RCV004764929 | SCV005375004 | likely pathogenic | Dilated cardiomyopathy 1G | 2024-01-06 | no assertion criteria provided | clinical testing |