VCV000810578.54 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(5)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 810578 Accession: VCV000810578.54

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xp11.4 X: 41578377 (GRCh38) [ NCBI UCSC ] X: 41437630 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Feb 3, 2020	Oct 20, 2024	Jul 30, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001367721.1:c.1466G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001354650.1:p.Arg489Gln	missense
NM_001126054.3:c.1466G>A	NP_001119526.1:p.Arg489Gln	missense
NM_001126055.3:c.1448G>A	NP_001119527.1:p.Arg483Gln	missense
NM_001410745.1:c.1448G>A	NP_001397674.1:p.Arg483Gln	missense
NM_003688.4:c.1466G>A	NP_003679.2:p.Arg489Gln	missense
NC_000023.11:g.41578377C>T
NC_000023.10:g.41437630C>T
NG_016754.2:g.349658G>A

... more HGVS ... less HGVS

Protein change

R483Q, R489Q

Other names

Canonical SPDI

NC_000023.11:41578376:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

dbSNP: rs1602292076 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
CASK		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	759	991

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Dec 13, 2023	RCV000999405.27
FG syndrome 4	Likely pathogenic (1)	criteria provided, single submitter	Jul 30, 2024	RCV001253354.5
Abnormality of the nervous system	Likely pathogenic (1)	criteria provided, single submitter	Jul 10, 2021	RCV001814250.4
Intellectual disability, CASK-related, X-linked	Pathogenic (1)	criteria provided, single submitter	Jun 22, 2023	RCV003624437.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Jul 10, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Abnormality of the nervous system Affected status: yes Allele origin: germline	Kariminejad - Najmabadi Pathology & Genetics Center Accession: SCV001755135.1 First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022
Pathogenic (Jun 22, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Intellectual disability, CASK-related, X-linked Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004551795.1 First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024	Publications: PubMed (3) PubMed: 27799067‚ 33090494‚ 30525188 Comment: 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 … (more) 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). (less)
Likely pathogenic (Dec 13, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001988443.3 First in ClinVar: Nov 06, 2021 Last updated: Oct 08, 2024	Comment: Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more) Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33090494, 30525188) (less)
Likely pathogenic (Jul 30, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	FG syndrome 4 (X-linked recessive inheritance) Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001429026.2 First in ClinVar: Aug 16, 2020 Last updated: Oct 13, 2024	Comment: Criteria applied: PS4_MOD,PM2,PM5,PP2 Clinical Features: Severe global developmental delay (present) , Difficulty walking (present) , Generalized-onset seizure (present) , Absent speech (present) Sex: male
Likely pathogenic (Mar 01, 2019)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001156006.27 First in ClinVar: Feb 03, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 1

Comment:

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).

Comment:

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33090494, 30525188)

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Missense mutations in CASK, coding for the calcium-/calmodulin-dependent serine protein kinase, interfere with neurexin binding and neurexin-induced oligomerization.	Pan YE	Journal of neurochemistry	2021	PMID: 33090494
Diagnostic exome sequencing in 100 consecutive patients with both epilepsy and intellectual disability.	Snoeijen-Schouwenaars FM	Epilepsia	2019	PMID: 30525188
Identification of a RAI1-associated disease network through integration of exome sequencing, transcriptomics, and 3D genomics.	Loviglio MN	Genome medicine	2016	PMID: 27799067

Text-mined citations for rs1602292076 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 20, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1602292076 ...