VCV000975413.8 - ClinVar

NM_001161352.2(KCNMA1):c.2588C>T (p.Pro863Leu)

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_001161352.2(KCNMA1):c.2588C>T (p.Pro863Leu)

Variation ID: 975413 Accession: VCV000975413.8

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 10q22.3 10: 78709021 (GRCh37) [ NCBI UCSC ] 10: 76949263 (GRCh38) [ 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	Aug 15, 2020	Dec 24, 2023	Dec 19, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001161352.2:c.2588C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001154824.1:p.Pro863Leu	missense
NM_001014797.3:c.2426C>T	NP_001014797.1:p.Pro809Leu	missense
NM_001161353.2:c.2537C>T	NP_001154825.1:p.Pro846Leu	missense
NM_001271518.2:c.2264C>T	NP_001258447.1:p.Pro755Leu	missense
NM_001271519.1:c.2423C>T
NM_001271519.2:c.2423C>T	NP_001258448.1:p.Pro808Leu	missense
NM_001322829.2:c.2423C>T	NP_001309758.1:p.Pro808Leu	missense
NM_001322830.2:c.2435C>T	NP_001309759.1:p.Pro812Leu	missense
NM_001322832.2:c.2414C>T	NP_001309761.1:p.Pro805Leu	missense
NM_001322835.2:c.2426C>T	NP_001309764.1:p.Pro809Leu	missense
NM_001322836.2:c.2423C>T	NP_001309765.1:p.Pro808Leu	missense
NM_001322837.2:c.2426C>T	NP_001309766.1:p.Pro809Leu	missense
NM_001322838.2:c.1961C>T	NP_001309767.1:p.Pro654Leu	missense
NM_002247.3:c.2414C>T
NM_002247.4:c.2414C>T	NP_002238.2:p.Pro805Leu	missense
NC_000010.11:g.76949263G>A
NC_000010.10:g.78709021G>A
NG_012270.1:g.693557C>T

... more HGVS ... less HGVS

Protein change

P654L, P755L, P805L, P808L, P809L, P812L, P846L, P863L

Other names

Canonical SPDI

NC_000010.11:76949262:G:A

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.

The Genome Aggregation Database (gnomAD), exomes 0.00000

Trans-Omics for Precision Medicine (TOPMed) 0.00000

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

Links

dbSNP: rs150678882 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.
KCNMA1		-	-	GRCh38 GRCh37	916	1325
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 benign (1)	no assertion criteria provided	Jan 1, 2019	RCV001252026.3
KCNMA1-related disorder	Pathogenic (1)	criteria provided, single submitter	Nov 16, 2020	RCV001420997.2
not provided	Likely pathogenic (1)	criteria provided, single submitter	Apr 4, 2023	RCV001751518.4
Liang-Wang syndrome	Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Dec 19, 2023	RCV001775159.4

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 (Nov 16, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	KCNMA1-related disorders Affected status: yes Allele origin: de novo	Centre of Medical Genetics, University of Antwerp Accession: SCV001448195.1 First in ClinVar: May 23, 2021 Last updated: May 23, 2021	Publications: PubMed (1) PubMed: 31152168
Likely pathogenic (Oct 25, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Liang-Wang syndrome Affected status: yes Allele origin: germline	3billion Accession: SCV002011870.1 First in ClinVar: Nov 11, 2021 Last updated: Nov 11, 2021	Publications: PubMed (1) PubMed: 31152168 Comment: The variant has been previously reported as de novo insimilarly affected unrelated individual (PMID:31152168, PS2). The variant is observed at an extremely low frequency in … (more) The variant has been previously reported as de novo insimilarly affected unrelated individual (PMID:31152168, PS2). The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000004, PM2). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.621, 3Cnet:0.763, PP3). Therefore, this variant is classified as likley pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Delayed speech and language development (present) , Intellectual disability (present) , Delayed gross motor development (present) , Delayed fine motor development (present) , Intellectual disability … (more) Delayed speech and language development (present) , Intellectual disability (present) , Delayed gross motor development (present) , Delayed fine motor development (present) , Intellectual disability (present) (less)
Likely pathogenic (Apr 04, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001985252.3 First in ClinVar: Nov 06, 2021 Last updated: May 27, 2023	Comment: De novo variant with confirmed parentage in a patient referred to GeneDx (Liang et al., 2019); Not observed at significant frequency in large population cohorts … (more) De novo variant with confirmed parentage in a patient referred to GeneDx (Liang et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Published functional studies demonstrate a damaging effect on protein expression (Liang et al., 2019); This variant is associated with the following publications: (PMID: 31152168, 34499417) (less)
Likely pathogenic (Dec 19, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Liang-Wang syndrome (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV004176837.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023	Clinical Features: Macrocephaly (present) , Hypertelorism (present) , Broad forehead (present) , High forehead (present) , Delayed speech and language development (present) , Gynecomastia (present) , Intellectual … (more) Macrocephaly (present) , Hypertelorism (present) , Broad forehead (present) , High forehead (present) , Delayed speech and language development (present) , Gynecomastia (present) , Intellectual disability (present) , Hypotonia (present) , Delayed gross motor development (present) , Poor motor coordination (present) , Genu valgum (present) , High anterior hairline (present) , Delayed fine motor development (present) (less)
Likely benign (Jan 01, 2019)	no assertion criteria provided Method: clinical testing	Intellectual disability Affected status: yes Allele origin: inherited	Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille Accession: SCV001427773.1 First in ClinVar: Aug 15, 2020 Last updated: Aug 15, 2020	Publications: PubMed (1) PubMed: 25741868

Comment:

The variant has been previously reported as de novo insimilarly affected unrelated individual (PMID:31152168, PS2). The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000004, PM2). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.621, 3Cnet:0.763, PP3). Therefore, this variant is classified as likley pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

De novo variant with confirmed parentage in a patient referred to GeneDx (Liang et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Published functional studies demonstrate a damaging effect on protein expression (Liang et al., 2019); This variant is associated with the following publications: (PMID: 31152168, 34499417)

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
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.	Richards S	Genetics in medicine : official journal of the American College of Medical Genetics	2015	PMID: 25741868

Text-mined citations for rs150678882 ...

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.2588C>T (p.Pro863Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs150678882 ...