Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000558011 | SCV000642614 | uncertain significance | Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J | 2017-09-19 | criteria provided, single submitter | clinical testing | In summary, this is a novel silent change with uncertain impact on splicing. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. This variant identified in the TTN gene is located in the M band of the resulting protein (PMID: 25589632). It is unclear how this variant impacts the function of this protein. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a TTN-related disease. This sequence change affects codon 35764 of the TTN mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the TTN protein. |
| Stanford Center for Inherited Cardiovascular Disease, |
RCV000786250 | SCV000924999 | uncertain significance | not provided | 2017-03-30 | no assertion criteria provided | provider interpretation | Given that this is a silent change in a gene in which even the significance of missense changes is still emerging, we consider this variant a variant of uncertain significance (VUS) and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). This variant is novel: it has not been reported in the literature, in ClinVar, or in large population databases. It is unclear at this time what role, if any, TTN missense variants play in causing inherited cardiovascular disese. While truncating (nonsense, frameshift, etc.) variants in TTN have been implicated in dilated cardiomyopathy, the impact of missense variants in this gene remains unclear. In general population samples there is a high prevalence of rare or novel TTN missense variants, making it likely that testing anyone with this panel would uncover such a variant. As such we would generally consider all TTN missense variants to be variants of uncertain significance. The genomic coordinates for this variant are chr2:179393086. LRG exon number is 362, N2BA transcript is 311. It is located in the M-band, 100% spliced in, in an Ig-like domain. Another variant in the same exon (c.107377+1G>A; splice site variant) has previously been reported in their End-stage non-ischemic DCM population (cardiodb.org) According to the test report, "Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this is a novel silent change with uncertain impact on splicing. It has been classified as a Variant of Uncertain Significance". The alanine at codon 35764 is conserved across species, as are neighboring amino acids. This variant is not present in the in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. The average coverage at that site in gnomAD is 64x. |