Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory of Medical Genetics, |
RCV001730034 | SCV001976790 | likely pathogenic | Noonan syndrome 8 | 2021-08-10 | criteria provided, single submitter | clinical testing | PM2, PP2, PP3, PP4 |
| Victorian Clinical Genetics Services, |
RCV001730034 | SCV005087135 | uncertain significance | Noonan syndrome 8 | 2023-07-17 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with Noonan syndrome 8 (MIM#615355). Variants have been shown to result in enhanced ELK1 transactivation (PMID: 23791108). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from methionine to arginine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v2) (highest allele count: 2 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated Ras family domain (DECIPHER). (I) 0710 - Other missense variants comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. These alternative changes (p.(Met39Thr), p.(Met39Lys), p.(Met39Val)) have been reported as VUSs (ClinVar), where one was observed in an individual with hypertrophic cardiomyopathy (personal communication). (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported as de novo and likely pathogenic, in an individual with pulmonary valve stenosis (ClinVar, personal communication). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |