Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV001356085 | SCV003011621 | pathogenic | not provided | 2022-09-06 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 1049672). Disruption of this splice site has been observed in individual(s) with clinical features of Usher syndrome (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 44 of the USH2A gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in USH2A are known to be pathogenic (PMID: 10729113, 10909849, 20507924, 25649381). |
Department of Pathology and Laboratory Medicine, |
RCV001356085 | SCV001551148 | likely pathogenic | not provided | no assertion criteria provided | clinical testing | The USH2A c.8845+2T>G variant was not identified in the literature nor was it identified in ClinVar, Cosmic, or LOVD 3.0, however the variant was identified in dbSNP (ID: rs1441350225). The variant was also not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.8845+2T>G variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. In addition, 4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing and the loss of the canonical 5' splice site. All programs predict the gain of a new 5' splice site four base pairs downstream of the canonical 5' splice site. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic. |