Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Victorian Clinical Genetics Services, |
RCV004595315 | SCV005086480 | likely pathogenic | Developmental delay, hypotonia, and impaired language | 2023-07-17 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with developmental delay, hypotonia, and impaired language (MIM#620012). However, additional mechanisms for missense variants have not been excluded (PMID: 35395208). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Variants that segregated within families displayed intrafamilial variability (PMID: 35395208). (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0601 - Variant results in the partial loss of the WD40 domain (DECIPHER). Additionally, functional studies have proven that missense variation in the truncated C-terminal region can impact protein function (PMID: 35395208). (SP) 0704 - Another protein truncating variant comparable to the one identified in this case has limited previous evidence for pathogenicity. A truncating variant (p.(Lys647*)) has been reported as likely pathogenic, and observed as de novo in an individual with a milder neurodevelopmental syndrome (ClinVar, PMID: 35395208). Another truncating variant (p.(Ser641*)), has been reported as a VUS in an individual with unknown inheritance and features including hypotonia with motor delay (DECIPHER). (SP) 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) 1207 - Parental origin of the variant is unresolved (by duo analysis). This variant is not maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |