VCV003068628.1 - ClinVar

NM_001161352.2(KCNMA1):c.2173del (p.Ser725fs)

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.

(1)

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, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001161352.2(KCNMA1):c.2173del (p.Ser725fs)

Variation ID: 3068628 Accession: VCV003068628.1

Type and length

Deletion, 1 bp

Location

Cytogenetic: 10q22.3 10: 77001500 (GRCh38) [ NCBI UCSC ] 10: 78761258 (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	Apr 15, 2024	Apr 15, 2024	Feb 4, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_001161352.2:c.2173del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001154824.1:p.Ser725fs	frameshift
NM_001161352.2:c.2173delT MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		frameshift
NM_001014797.3:c.2104+10467del		intron variant
NM_001161353.2:c.2092+10467del		intron variant
NM_001271518.2:c.1942+10467del		intron variant
NM_001271519.2:c.2101+6685del		intron variant
NM_001322829.2:c.2101+6685del		intron variant
NM_001322830.2:c.2113+6685del		intron variant
NM_001322832.2:c.2092+10467del		intron variant
NM_001322835.2:c.2104+10467del		intron variant
NM_001322836.2:c.2101+6685del		intron variant
NM_001322837.2:c.2104+10467del		intron variant
NM_001322838.2:c.1552+10467del		intron variant
NM_001410940.1:c.2092+10467del		intron variant
NM_002247.4:c.2092+10467del		intron variant
NC_000010.11:g.77001500del
NC_000010.10:g.78761258del
NG_012270.1:g.641320del

... more HGVS ... less HGVS

Protein change

S725fs

Other names

Canonical SPDI

NC_000010.11:77001499: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.

Links

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	910	1316

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.
Cerebellar atrophy, developmental delay, and seizures	Likely pathogenic (1)	criteria provided, single submitter	Feb 4, 2022	RCV003994697.1

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 (Feb 04, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cerebellar atrophy, developmental delay, and seizures Affected status: unknown Allele origin: germline	Molecular Genetics, Royal Melbourne Hospital Additional submitter: Shariant Australia, Australian Genomics Accession: SCV004812683.1 First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024	Publications: PubMed (1) PubMed: 34224328 Comment: This sequence change in KCNMA1 is a frameshift variant predicted to cause a premature stop codon, p.(Ser725Glnfs61), in biologically-relevant-exon 20/28 leading to nonsense mediated decay … (more) This sequence change in KCNMA1 is a frameshift variant predicted to cause a premature stop codon, p.(Ser725Glnfs61), in biologically-relevant-exon 20/28 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PMID: 34224328). This variant is present in a single European (nono-Finnish) individual in gnomAD v2.1 (1/61,344 alleles). To our knowledge, this variant has not been reported in the literature in any individuals with KCNMA1-related disease. Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PVS1, PM2_Supporting. (less)

Comment:

This sequence change in KCNMA1 is a frameshift variant predicted to cause a premature stop codon, p.(Ser725Glnfs*61), in biologically-relevant-exon 20/28 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PMID: 34224328). This variant is present in a single European (nono-Finnish) individual in gnomAD v2.1 (1/61,344 alleles). To our knowledge, this variant has not been reported in the literature in any individuals with KCNMA1-related disease. Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PVS1, PM2_Supporting.

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
An emerging spectrum of variants and clinical features in KCNMA1-linked channelopathy.	Miller JP	Channels (Austin, Tex.)	2021	PMID: 34224328

Text-mined citations for this variant ...

Record last updated Apr 20, 2024

ClinVar Genomic variation as it relates to human health

NM_001161352.2(KCNMA1):c.2173del (p.Ser725fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...