Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV001267225 | SCV001445406 | likely pathogenic | Inborn genetic diseases | 2020-09-25 | criteria provided, single submitter | clinical testing | The c.821-1G>A intronic alteration consists of a G to A substitution one nucleotide before coding exon 2 of the CDKN1C gene. This alteration occurs at the 3' terminus of the CDKN1C gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 43 amino acids (13.6%) of the protein. The exact functional effect of this alteration is unknown; however, the impacted region is critical for protein function and a significant portion of the protein is affected (Ambry internal data). for Beckwith-Wiedemann syndrome; however, its clinical significance for autosomal dominant IMAGe syndrome is uncertain. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Another alteration impacting the same acceptor site (c.821-2A>G) has been described in a patient with features consistent with Beckwith-Wiedemann syndrome including overgrowth, mild macroglossia, flat vascular malformation in glabella, omphalocele, and inguinal hernia (Romanelli, 2010). This nucleotide position is highly conserved in available vertebrate species. The resulting truncated protein from the c.821-1G>A alteration is predicted to be missing the PCNA-binding domain (Arboleda, 2012). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. Based on the available evidence, this alteration is classified as likely pathogenic. |