Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV001759718 | SCV001996149 | uncertain significance | not provided | 2019-09-25 | criteria provided, single submitter | clinical testing | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge |
Victorian Clinical Genetics Services, |
RCV001027719 | SCV002767929 | uncertain significance | Intellectual disability, X-linked 49 | 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 Raynaud-Claes syndrome (MIM#300114). (I) 0110 - This gene is associated with X-linked dominant disease. (OMIM, PMID: 27550844). (I) 0115 - Variants in this gene are known to have variable expressivity. (PMID: 27550844). (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to leucine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (v2: 1 heterozygote, 0 homozygotes, 0 hemizygotes) (v3: 0 heterozygote, 0 homozygotes, 1 hemizygote). (SP) 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 (PDB). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0803 - This variant has limited previous evidence of pathogenicity in an individual (ClinVar). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) |
Invitae | RCV001759718 | SCV003027433 | uncertain significance | not provided | 2022-07-06 | criteria provided, single submitter | clinical testing | 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 827824). This variant has not been reported in the literature in individuals affected with CLCN4-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.005%), including at least one homozygous and/or hemizygous individual. This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 684 of the CLCN4 protein (p.Pro684Leu). |
Equipe Genetique des Anomalies du Developpement, |
RCV001027719 | SCV001190303 | uncertain significance | Intellectual disability, X-linked 49 | 2022-10-21 | no assertion criteria provided | clinical testing |