Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV001266967 | SCV001445148 | uncertain significance | Inborn genetic diseases | 2021-08-09 | criteria provided, single submitter | clinical testing | The c.667A>G (p.I223V) alteration is located in coding exon 7 of the UPF3B gene. This alteration results from an A to G substitution at nucleotide position 667, causing the isoleucine (I) at amino acid position 223 to be replaced by a valine (V). Based on data from gnomAD, the V allele has an overall frequency of 0.002% (4/179,516) total alleles studied, with 1 hemizygote observed. The highest observed frequency was 0.004% (3/79,387) of European (non-Finnish) alleles. However, this variant is found in a low complexity region. This amino acid position is not well conserved in available vertebrate species. This alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. |
| Victorian Clinical Genetics Services, |
RCV002272438 | SCV002557402 | uncertain significance | Syndromic X-linked intellectual disability 14 | 2022-02-02 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with UPF3B-related syndromic intellectual disability (MIM#300676). (I) 0109 - This gene is associated with X-linked recessive disease. Female carriers have skewed X-inactivation favouring expression of wild type allele (PMID: 26012578). (I) 0115 - Variants in this gene are known to have variable expressivity. It is associated with a phenotypic spectrum and intellectual disability can range from mild to severe (PMID: 26012578, OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from isoleucine to valine. (I) 0253 - This variant is hemizygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (3 heterozygotes, 0 homozygotes, 1 hemizygote). (SP) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. It has been classified a VUS (ClinVar) and it has been reported in an individual with intellectual disability who harboured many other variants, including a nonsense variant in the KDM5C gene which was regarded as the likely cause of the condition (PMID: 26350204). (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 |
| Labcorp Genetics |
RCV002272438 | SCV003520667 | benign | Syndromic X-linked intellectual disability 14 | 2023-12-24 | criteria provided, single submitter | clinical testing |