VCV000978933.3 - ClinVar

NM_001161352.2(KCNMA1):c.3022G>A (p.Asp1008Asn)

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.

(3)

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.

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_001161352.2(KCNMA1):c.3022G>A (p.Asp1008Asn)

Variation ID: 978933 Accession: VCV000978933.3

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 10q22.3 10: 76910091 (GRCh38) [ NCBI UCSC ] 10: 78669849 (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	Jan 13, 2020	Jul 23, 2024	Dec 15, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001161352.2:c.3022G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001154824.1:p.Asp1008Asn	missense
NM_001014797.3:c.2860G>A	NP_001014797.1:p.Asp954Asn	missense
NM_001161353.2:c.2971G>A	NP_001154825.1:p.Asp991Asn	missense
NM_001271518.2:c.2698G>A	NP_001258447.1:p.Asp900Asn	missense
NM_001271519.2:c.2938G>A	NP_001258448.1:p.Asp980Asn	missense
NM_001322829.2:c.2857G>A	NP_001309758.1:p.Asp953Asn	missense
NM_001322830.2:c.2950G>A	NP_001309759.1:p.Asp984Asn	missense
NM_001322832.2:c.2848G>A	NP_001309761.1:p.Asp950Asn	missense
NM_001322835.2:c.2941G>A	NP_001309764.1:p.Asp981Asn	missense
NM_001322836.2:c.2857G>A	NP_001309765.1:p.Asp953Asn	missense
NM_001322837.2:c.2941G>A	NP_001309766.1:p.Asp981Asn	missense
NM_001322838.2:c.2395G>A	NP_001309767.1:p.Asp799Asn	missense
NM_002247.3:c.2848G>A
NM_002247.4:c.2848G>A	NP_002238.2:p.Asp950Asn	missense
NC_000010.11:g.76910091C>T
NC_000010.10:g.78669849C>T
NG_012270.1:g.732729G>A

... more HGVS ... less HGVS

Protein change

D1008N, D799N, D900N, D950N, D953N, D954N, D980N, D981N, D984N, D991N

Other names

Canonical SPDI

NC_000010.11:76910090: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

OMIM: 600150.0011 dbSNP: rs2049489016 VarSome

Comment on variant

NCBI staff provided an HGVS expression for 600150.0011 to be consistent with the sequence context of the Asp residue reported in Figure 5 of the paper by Liang et al., 2019 (PubMed 31152168).

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.
Intellectual disability	Likely pathogenic (1)	criteria provided, single submitter	Apr 20, 2020	RCV001257729.2
Liang-Wang syndrome	Pathogenic (1)	no assertion criteria provided	Jan 10, 2020	RCV002269354.2
not provided	Likely pathogenic (1)	criteria provided, single submitter	Dec 15, 2023	RCV004590285.1

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 (Apr 20, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Intellectual disability (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Diagnostic Laboratory, Strasbourg University Hospital Accession: SCV001434541.1 First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020	Age: 0-9 years Sex: male Tissue: blood Method: targeted capture
Likely pathogenic (Dec 15, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV005079316.1 First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024	Comment: Published functional studies suggest a damaging effect with reduced current amplitude (PMID: 31152168); Not observed at significant frequency in large population cohorts (gnomAD); In silico … (more) Published functional studies suggest a damaging effect with reduced current amplitude (PMID: 31152168); 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: 31152168) (less)
Pathogenic (Jan 10, 2020)	no assertion criteria provided Method: literature only	LIANG-WANG SYNDROME Affected status: not provided Allele origin: germline	OMIM Accession: SCV001142652.1 First in ClinVar: Jan 13, 2020 Last updated: Jan 13, 2020	Publications: PubMed (1) PubMed: 31152168 Comment on evidence: In a 4-year-old boy (patient 9) with a mild form of Liang-Wang syndrome (LIWAS; 618729), Liang et al. (2019) identified a de novo heterozygous mutation … (more) In a 4-year-old boy (patient 9) with a mild form of Liang-Wang syndrome (LIWAS; 618729), Liang et al. (2019) identified a de novo heterozygous mutation in the KCNMA1 gene, resulting in an asp984-to-asn (D984N) substitution at a highly conserved residue in the RCK2 domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC, gnomAD, 1000 Genomes Project, or Exome Variant Server databases. Patch-clamp experiments in transfected HEK293 cells showed that the mutation decreased the current amplitude of the BK channel without affecting kinetics. The findings were consistent with a partial loss-of-function effect. (less)

Comment:

Published functional studies suggest a damaging effect with reduced current amplitude (PMID: 31152168); 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: 31152168)

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 loss-of-function KCNMA1 variants are associated with a new multiple malformation syndrome and a broad spectrum of developmental and neurological phenotypes.	Liang L	Human molecular genetics	2019	PMID: 31152168

Text-mined citations for rs2049489016 ...

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 Aug 18, 2024

ClinVar Genomic variation as it relates to human health

NM_001161352.2(KCNMA1):c.3022G>A (p.Asp1008Asn)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs2049489016 ...