Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000520219 | SCV000622062 | uncertain significance | not provided | 2018-05-30 | criteria provided, single submitter | clinical testing | The E1333G variant in the ZNF335 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. While not seen in the homozygous state, the E1333G variant is observed in 27/126596 (0.02%) alleles in large population cohorts (Lek et al., 2016). The E1333G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret E1333G as a variant of uncertain significance. |
| Victorian Clinical Genetics Services, |
RCV000709924 | SCV002768907 | uncertain significance | Microcephalic primordial dwarfism due to ZNF335 deficiency | 2021-05-06 | 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: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with primary microcephaly 10 (MIM#615095). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to glycine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (36 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (9 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 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. This variant has been reported as VUS in a patient with microcephaly (ClinVar, PMID: 29652087). (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) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |
| Fulgent Genetics, |
RCV000709924 | SCV002788875 | uncertain significance | Microcephalic primordial dwarfism due to ZNF335 deficiency | 2022-03-02 | criteria provided, single submitter | clinical testing | |
| Genome |
RCV000709924 | SCV000840269 | not provided | Microcephalic primordial dwarfism due to ZNF335 deficiency | no assertion provided | phenotyping only | GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. | |
| OMIM | RCV000709924 | SCV000886425 | pathogenic | Microcephalic primordial dwarfism due to ZNF335 deficiency | 2019-02-19 | no assertion criteria provided | literature only |