ClinVar Miner

Submissions for variant NM_001830.4(CLCN4):c.2051C>T (p.Pro684Leu)

gnomAD frequency: 0.00001  dbSNP: rs1246068842
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx 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, Murdoch Childrens Research Institute 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, Université de Bourgogne RCV001027719 SCV001190303 uncertain significance Intellectual disability, X-linked 49 2022-10-21 no assertion criteria provided clinical testing

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