Total submissions: 1
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Victorian Clinical Genetics Services, |
RCV002470282 | SCV002767014 | uncertain significance | Shukla-Vernon syndrome | 2022-09-02 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. However, loss of function is unlikely to be the mechanism for germline disease (PMID: 35178361). (I) 0109 - This gene is associated with X-linked recessive disease. However, females may be mildly affected (PMID: 33810051). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0253 - This variant is hemizygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative NMD-predicted variant has been observed in gnomAD (v2) (3 heterozygotes, 0 homozygotes, 1 hemizygote). (I) 0710 - Other NMD-predicted variants comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. These variants have been reported once as pathogenic but more often as VUS (LOVD, DECIPHER, ClinVar) in individuals with features including intellectual disability or renal agenesis. However, NMD-predicted variants have been more commonly reported in cohorts with myelodysplastic syndromes, myeloma or intracranial germ cell tumors (ClinVar, PMID: 24896186, PMID: 24047651, PMID: 27470916). (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 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 |