Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000578936 | SCV000681304 | likely pathogenic | not provided | 2018-09-12 | criteria provided, single submitter | clinical testing | The Y31000X variant is not observed in large population cohorts (Lek et al., 2016). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Although Y31000X has not been previously reported to our knowledge, other nonsense variants in the TTN gene have been reported in the Human Gene Mutation Database in association with TTN-related disorders (Stenson et al., 2014). Additionally, the Y31000X variant is located in the A-band of the titin protein, where the majority of pathogenic truncating variants have been reported. |
| Ambry Genetics | RCV002384275 | SCV002671113 | likely pathogenic | Cardiovascular phenotype | 2019-08-01 | criteria provided, single submitter | clinical testing | The p.Y24503* variant (also known as c.73509C>A), located in coding exon 184 of the TTN gene, results from a C to A substitution at nucleotide position 73509. This changes the amino acid from a tyrosine to a stop codon within coding exon 184. 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. |
| Genome |
RCV000844995 | SCV000986825 | not provided | Myopathy, myofibrillar, 9, with early respiratory failure | no assertion provided | phenotyping only | Variant interpretted as Likely pathogenic and reported on 01/12/2018 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. |