Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000599585 | SCV000710490 | uncertain significance | not provided | 2018-01-30 | criteria provided, single submitter | clinical testing | A variant of uncertain significance has been identified in the TTN gene. The c.41066dupT variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016). The c.41066dupT variant causes a shift in reading frame starting at codon threonine 13690, changing it to an asparagine, and creating a premature stop codon at position 9 of the new reading frame, denoted p.Thr13690AsnfsX9. This variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Nevertheless, other truncating TTN variants have been reported in approximately 3% of control alleles (Herman et al., 2012). Additionally, c.41066dupT is located in the I-band region of titin, while the majority of truncating pathogenic variants have been reported in the A-band region of titin (Herman et al., 2012). |
| Invitae | RCV000642742 | SCV000764429 | uncertain significance | Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J | 2017-08-27 | criteria provided, single submitter | clinical testing | This variant identified in the TTN gene is located in the I band of the resulting protein (PMID: 25589632). In summary, although this is a novel truncating variant, truncating variants in this region of the TTN gene have been shown to be highly prevalent in the TTN gene in the general population and unaffected individuals (PMID: 26701604, 22335739). However, truncating mutations in this region have also been reported to cause autosomal recessive congenital myopathy (PMID: 23975875). Therefore without additional functional and/or genetic data, this variant has been classified as a Variant of Uncertain Significance. This variant has not been reported in the literature in individuals with TTN-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Thr15331Asnfs*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. |
| Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, |
RCV001256703 | SCV001433106 | likely pathogenic | Dilated cardiomyopathy 1A | 2019-01-29 | criteria provided, single submitter | clinical testing |