Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001380060 | SCV001577995 | pathogenic | Beckwith-Wiedemann syndrome | 2022-06-20 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 35531). This missense change has been observed in individual(s) with IMAGe syndrome (PMID: 22634751, 24313804). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 274 of the CDKN1C protein (p.Asp274Asn). This variant also falls at the last nucleotide of exon 1, which is part of the consensus splice site for this exon. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies have shown that this missense change affects CDKN1C function (PMID: 24098681). |
| Ambry Genetics | RCV002513231 | SCV003646515 | pathogenic | Inborn genetic diseases | 2022-10-28 | criteria provided, single submitter | clinical testing | The c.820G>A (p.D274N) alteration is located in exon 1 (coding exon 1) of the CDKN1C gene. This alteration results from a G to A substitution at nucleotide position 820, causing the aspartic acid (D) at amino acid position 274 to be replaced by an asparagine (N)._x000D_ _x000D_ Based on the available evidence, the CDKN1C c.820G>A (p.D274N) alteration is classified as pathogenic for IMAGE syndrome; however, this variant is unlikely to be causative of Beckwith-Wiedemann syndrome. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been observed in multiple unrelated individuals with IMAGE syndrome and has been reported as de novo and maternally inherited (Arboleda, 2012; Kato, 2014; Amano, 2017; Homma, 2019; Bolomiti, 2021). This amino acid position is well conserved in available vertebrate species with limited sequence alignment. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). Functional assays modestly suggest that protein stability is increased, but additional evidence is needed to confirm these data (Hamajima, 2013). This alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. |
| OMIM | RCV004814928 | SCV000051831 | pathogenic | IMAGe syndrome | 2012-05-27 | no assertion criteria provided | literature only |