ClinVar Miner

Submissions for variant NM_001367721.1(CASK):c.1466G>A (p.Arg489Gln)

dbSNP: rs1602292076
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Center for Human Genetics Tuebingen RCV000999405 SCV001156006 likely pathogenic not provided 2019-03-01 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV001253354 SCV001429026 likely pathogenic FG syndrome 4 2018-12-04 criteria provided, single submitter clinical testing This variant was identified as hemizygous
Kariminejad - Najmabadi Pathology & Genetics Center RCV001814250 SCV001755135 likely pathogenic Abnormality of the nervous system 2021-07-10 criteria provided, single submitter clinical testing
GeneDx RCV000999405 SCV001988443 uncertain significance not provided 2019-05-21 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30525188)
Invitae RCV003624437 SCV004551795 pathogenic Intellectual disability, CASK-related, X-linked 2023-06-22 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg489 amino acid residue in CASK. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27799067, 33090494). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CASK protein function. ClinVar contains an entry for this variant (Variation ID: 810578). This missense change has been observed in individual(s) with clinical features of developmental and epileptic encephalopathy, intellectual disability, and/or seizures (PMID: 30525188; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 489 of the CASK protein (p.Arg489Gln).

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