VCV000265313.35 - ClinVar

NM_001161352.2(KCNMA1):c.3158A>G (p.Asn1053Ser)

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.

(7)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001161352.2(KCNMA1):c.3158A>G (p.Asn1053Ser)

Variation ID: 265313 Accession: VCV000265313.35

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 10q22.3 10: 76891709 (GRCh38) [ NCBI UCSC ] 10: 78651467 (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	Sep 2, 2017	Oct 20, 2024	Dec 22, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001161352.2:c.3158A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001154824.1:p.Asn1053Ser	missense
NM_001014797.3:c.2996A>G	NP_001014797.1:p.Asn999Ser	missense
NM_001161353.2:c.3107A>G	NP_001154825.1:p.Asn1036Ser	missense
NM_001271518.2:c.2834A>G	NP_001258447.1:p.Asn945Ser	missense
NM_001271519.2:c.3074A>G	NP_001258448.1:p.Asn1025Ser	missense
NM_001322829.2:c.2993A>G	NP_001309758.1:p.Asn998Ser	missense
NM_001322830.2:c.3086A>G	NP_001309759.1:p.Asn1029Ser	missense
NM_001322832.2:c.2984A>G	NP_001309761.1:p.Asn995Ser	missense
NM_001322835.2:c.3077A>G	NP_001309764.1:p.Asn1026Ser	missense
NM_001322836.2:c.2993A>G	NP_001309765.1:p.Asn998Ser	missense
NM_001322837.2:c.3077A>G	NP_001309766.1:p.Asn1026Ser	missense
NM_001322838.2:c.2531A>G	NP_001309767.1:p.Asn844Ser	missense
NM_002247.2:c.2984A>G
NM_002247.4:c.2984A>G	NP_002238.2:p.Asn995Ser	missense
NC_000010.11:g.76891709T>C
NC_000010.10:g.78651467T>C
NG_012270.1:g.751111A>G

... more HGVS ... less HGVS

Protein change

N995S, N999S, N1053S, N1025S, N1026S, N1029S, N1036S, N844S, N945S, N998S

Other names

Canonical SPDI

NC_000010.11:76891708:T:C

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

ClinGen: CA10588480 OMIM: 600150.0003 dbSNP: rs886039469 VarSome

Comment on variant

NCBI staff established the molecular definition of 600150.0003 based on supplementary data for the paper by Zhang et al. (PubMed 26195193).

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.
KCNMA1		-	-	GRCh38 GRCh37	920	1329
KCNMA1-AS1	-	-	-	GRCh38	-	391

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	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jan 3, 2023	RCV000255423.22
Generalized epilepsy-paroxysmal dyskinesia syndrome	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Dec 22, 2023	RCV000504575.14

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.
Pathogenic (Jan 03, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000322055.8 First in ClinVar: Oct 10, 2016 Last updated: Jan 15, 2023	Comment: Published functional studies demonstrate that N995S results in a gain-of-function with markedly increased macroscopic potassium current (Li et al., 2018; Moldenhauer et al., 2020); In … (more) Published functional studies demonstrate that N995S results in a gain-of-function with markedly increased macroscopic potassium current (Li et al., 2018; Moldenhauer et al., 2020); 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); Also known as N1053S using alternate nomenclature; This variant is associated with the following publications: (PMID: 32132200, 32655623, 26195193, 29330545, 30525188, 31152168, 31851553, 32633875, 33043086, 33767182) (less)
Pathogenic (Feb 01, 2022)	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: SCV002497043.18 First in ClinVar: Apr 08, 2022 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Pathogenic (Oct 05, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Generalized epilepsy-paroxysmal dyskinesia syndrome (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Undiagnosed Diseases Network, NIH Accession: SCV000863433.1 First in ClinVar: Oct 10, 2018 Last updated: Oct 10, 2018	Number of individuals with the variant: 1 Clinical Features: Weak cry (present) , Upgaze palsy (present) , Unilateral ptosis (present) , Umbilical hernia (present) , Speech articulation difficulties (present) , Severe Myopia (present) , … (more) Weak cry (present) , Upgaze palsy (present) , Unilateral ptosis (present) , Umbilical hernia (present) , Speech articulation difficulties (present) , Severe Myopia (present) , Reduced brain N-acetyl aspartate level by MRS (present) , Recurrent upper respiratory tract infections (present) , Prenatal maternal abnormality (present) , Meconium stained amniotic fluid (present) , Laryngomalacia (present) , Intrauterine growth retardation (present) , Increased axial globe length (present) , Hypoglycemia (present) , Hyperpigmentation of the skin (present) , Hyperbilirubinemia (present) , Hydronephrosis (present) , Generalized joint laxity (present) , Facial palsy (present) , Epicanthus (present) , EEG abnormality (present) , Dry skin (present) , Depressed nasal bridge (present) , Delayed fine motor development (present) , Cyanotic episode (present) , Cranial nerve VI palsy (present) , Cognitive impairment (present) , Cataplexy (present) , Atonic seizures (present) , Asymmetric crying face (present) , Abnormality of the renal collecting system (present) , Abnormality of the nail (present) , Abnormality of the aryepiglottic fold (present) (less) Age: 0-9 years Sex: female Ethnicity/Population group: African American Tissue: blood Testing laboratory: HudsonAlpha Clinical Services Lab, LLC,HudsonAlpha Clinical Services Lab, LLC Date variant was reported to submitter: 2017-08-23 Testing laboratory interpretation: Pathogenic
Pathogenic (Dec 22, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Generalized epilepsy-paroxysmal dyskinesia syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000830549.7 First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 28492532‚ 26195193‚ 29330545 Comment: This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 995 of the KCNMA1 protein (p.Asn995Ser). … (more) This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 995 of the KCNMA1 protein (p.Asn995Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with epilepsy and/or paroxysomal dyskinesia (PMID: 26195193, 29330545; Invitae). In at least one individual the variant was observed to be de novo. This variant is also known as c.3158A>G (p.Asn1053Ser). ClinVar contains an entry for this variant (Variation ID: 265313). 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 KCNMA1 protein function. Experimental studies have shown that this missense change affects KCNMA1 function (PMID: 29330545). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Aug 30, 2017)	no assertion criteria provided Method: literature only	PAROXYSMAL NONKINESIGENIC DYSKINESIA, 3, WITH OR WITHOUT GENERALIZED EPILEPSY Affected status: not provided Allele origin: germline	OMIM Accession: SCV000598623.1 First in ClinVar: Sep 02, 2017 Last updated: Sep 02, 2017	Publications: PubMed (1) PubMed: 26195193 Comment on evidence: In a Chinese boy with paroxysmal nonkinesigenic dyskinesia-3 without generalized epilepsy (PNKD3; 609446), Zhang et al. (2015) identified a de novo heterozygous c.3158A-G transition in … (more) In a Chinese boy with paroxysmal nonkinesigenic dyskinesia-3 without generalized epilepsy (PNKD3; 609446), Zhang et al. (2015) identified a de novo heterozygous c.3158A-G transition in the KCNMA1 gene, resulting in an asn1053-to-ser (N1053S) substitution at a conserved residue. The mutation, which was found by targeted gene sequencing and confirmed by Sanger sequencing, was not found in 500 control samples. Functional studies of the variant and studies of patient cells were not performed. The patient had onset of isolated PNKD at 7 months of age and had mild developmental delay. (less)
Likely pathogenic (May 13, 2021)	no assertion criteria provided Method: clinical testing	Generalized epilepsy-paroxysmal dyskinesia syndrome Affected status: yes Allele origin: unknown	Pediatric Genetics Clinic, Sheba Medical Center Accession: SCV001712187.1 First in ClinVar: Dec 12, 2021 Last updated: Dec 12, 2021	Clinical Features: Global developmental delay (present) , Seizure (present) , Abnormal facial shape (present) Secondary finding: no
Likely pathogenic (Sep 08, 2002)	no assertion criteria provided Method: research	Generalized epilepsy-paroxysmal dyskinesia syndrome Affected status: yes Allele origin: unknown	Center of Excellence for Medical Genomics, Chulalongkorn University Accession: SCV002570056.1 First in ClinVar: Sep 10, 2022 Last updated: Sep 10, 2022

Comment:

Published functional studies demonstrate that N995S results in a gain-of-function with markedly increased macroscopic potassium current (Li et al., 2018; Moldenhauer et al., 2020); 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); Also known as N1053S using alternate nomenclature; This variant is associated with the following publications: (PMID: 32132200, 32655623, 26195193, 29330545, 30525188, 31152168, 31851553, 32633875, 33043086, 33767182)

Comment:

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 995 of the KCNMA1 protein (p.Asn995Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with epilepsy and/or paroxysomal dyskinesia (PMID: 26195193, 29330545; Invitae). In at least one individual the variant was observed to be de novo. This variant is also known as c.3158A>G (p.Asn1053Ser). ClinVar contains an entry for this variant (Variation ID: 265313). 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 KCNMA1 protein function. Experimental studies have shown that this missense change affects KCNMA1 function (PMID: 29330545). For these reasons, this variant has been classified as Pathogenic.

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
De novo BK channel variant causes epilepsy by affecting voltage gating but not Ca(2+) sensitivity.	Li X	European journal of human genetics : EJHG	2018	PMID: 29330545
De novo KCNMA1 mutations in children with early-onset paroxysmal dyskinesia and developmental delay.	Zhang ZB	Movement disorders : official journal of the Movement Disorder Society	2015	PMID: 26195193

Text-mined citations for rs886039469 ...

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_001161352.2(KCNMA1):c.3158A>G (p.Asn1053Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs886039469 ...