Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001871917 | SCV002130103 | uncertain significance | Nephronophthisis 14 | 2022-08-31 | criteria provided, single submitter | clinical testing | This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 424 of the ZNF423 protein (p.Val424Met). This variant is present in population databases (rs375353056, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with ZNF423-related conditions. ClinVar contains an entry for this variant (Variation ID: 1048870). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| Department of Pathology and Laboratory Medicine, |
RCV001354235 | SCV001548797 | uncertain significance | not provided | no assertion criteria provided | clinical testing | The ZNF423 p.Val307Met variant was not identified in the literature nor was it identified in ClinVar or Cosmic. The variant was identified in dbSNP (ID: rs375353056), LOVD 3.0 and in control databases in 18 of 251362 chromosomes at a frequency of 0.000072 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 9 of 30616 chromosomes (freq: 0.000294), Other in 1 of 6132 chromosomes (freq: 0.000163), Latino in 5 of 34590 chromosomes (freq: 0.000145), European (Finnish) in 1 of 21640 chromosomes (freq: 0.000046) and European (non-Finnish) in 2 of 113662 chromosomes (freq: 0.000018); it was not observed in the African, Ashkenazi Jewish, and East Asian populations. The p.Val307 residue is conserved in mammals but not in more distantly related organisms and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. |