Submissions for variant NM_001367721.1(CASK):c.764G>A (p.Arg255His)

dbSNP: rs587783369

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000145413	SCV000192502	likely pathogenic	Syndromic X-linked intellectual disability Najm type	2014-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000494524	SCV000583093	pathogenic	not provided	2024-05-17	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 36198807, 33057194, 35982159, 35550617, Zhang2023[Case Report], 32989192)
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000145413	SCV001164437	likely pathogenic	Syndromic X-linked intellectual disability Najm type	2018-12-03	criteria provided, single submitter	research	The hemizygous p.Arg255His variant in CASK was identified by our study in one individual with mental retardation and microcephaly with pontine and cerebellar hypoplasia. This variant was absent from large population studies. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The CASK gene has a low rate of benign missense variation and there is a different pathogenic missense variant at the same position, p.Arg255Cys. These support the possibility that an amino acid change at this position may not be tolerated. This variant has also been reported in ClinVar with de novo inheritance (Variation ID: 158084). In summary, although additional studies are required to fully establish its clinical significance, the p.Arg255His variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PM5, PP2, PM6 (Richards 2015).
Mendelics	RCV002247536	SCV002518637	pathogenic	FG syndrome 4	2022-05-04	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000494524	SCV003829223	uncertain significance	not provided	2023-05-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003764883	SCV004649207	uncertain significance	Intellectual disability, CASK-related, X-linked	2023-04-10	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 255 of the CASK protein (p.Arg255His). This variant is not present in population databases (gnomAD no frequency). 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. 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: 158084). This variant has not been reported in the literature in individuals affected with CASK-related conditions.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000145413	SCV005085891	pathogenic	Syndromic X-linked intellectual disability Najm type	2023-12-21	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with intellectual developmental disorder and microcephaly with pontine and cerebellar hypoplasia (MIM#300749) and intellectual disability with or without nystagmus (MIM#300422). (I) 0110 - This gene is associated with X-linked disease. However, intellectual developmental disorder, with or without nystagmus (MIM#300422) is associated with hypomorphic variants that typically cause symptoms in hemizygous males but not in heterozygous females (PMID: 24278995). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0253 - This variant is hemizygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic in ClinVar and as de novo in three unrelated individuals with CASK-related symptoms (ClinVar, PMID: 32989192, 35550617). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Center of Excellence for Medical Genomics, Chulalongkorn University	RCV002247536	SCV002570070	likely pathogenic	FG syndrome 4	2002-09-08	no assertion criteria provided	research