VCV000541052.18 - ClinVar

NM_000069.3(CACNA1S):c.1935C>T (p.Phe645=)

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.

(9)

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.

Benign/Likely benign

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000069.3(CACNA1S):c.1935C>T (p.Phe645=)

Variation ID: 541052 Accession: VCV000541052.18

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q32.1 1: 201075508 (GRCh38) [ NCBI UCSC ] 1: 201044636 (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	May 28, 2018	Oct 8, 2024	Dec 18, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000069.3:c.1935C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000060.2:p.Phe645=	synonymous
NC_000001.11:g.201075508G>A
NC_000001.10:g.201044636G>A
NG_009816.2:g.42059C>T

Protein change

Other names

Canonical SPDI

NC_000001.11:201075507: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.

0.00020 (A)

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

Trans-Omics for Precision Medicine (TOPMed) 0.00008

The Genome Aggregation Database (gnomAD) 0.00009

The Genome Aggregation Database (gnomAD), exomes 0.00010

Exome Aggregation Consortium (ExAC) 0.00012

1000 Genomes Project 0.00020

1000 Genomes Project 30x 0.00031

Links

ClinGen: CA078672 dbSNP: rs550584336 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.
CACNA1S		No evidence available	No evidence available	GRCh38 GRCh37	2683	2711

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.
Hypokalemic periodic paralysis, type 1 Malignant hyperthermia, susceptibility to, 5	Likely benign (1)	criteria provided, single submitter	Nov 25, 2023	RCV000651241.10
Hypokalemic periodic paralysis, type 1	Benign/Likely benign (2)	criteria provided, multiple submitters, no conflicts	Apr 11, 2023	RCV001096375.5
Malignant hyperthermia, susceptibility to, 5	Likely benign (2)	criteria provided, multiple submitters, no conflicts	Dec 18, 2023	RCV003451567.3
Congenital myopathy 18	Likely benign (1)	criteria provided, single submitter	Apr 11, 2023	RCV003458490.1
Thyrotoxic periodic paralysis, susceptibility to, 1	Likely benign (1)	criteria provided, single submitter	Apr 11, 2023	RCV003451568.1
CACNA1S-related disorder	Likely benign (1)	no assertion criteria provided	Jan 4, 2023	RCV003892480.2
not provided	Likely benign (1)	criteria provided, single submitter	-	RCV004711270.1

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.
Benign (Jan 12, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Hypokalemic periodic paralysis, type 1 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001252577.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
Likely benign (Nov 25, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hypokalemic periodic paralysis, type 1 Malignant hyperthermia, susceptibility to, 5 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000773092.7 First in ClinVar: May 28, 2018 Last updated: Feb 28, 2024
Likely benign (Apr 11, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Thyrotoxic periodic paralysis, susceptibility to, 1 Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV004178950.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023
Likely benign (Apr 11, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Malignant hyperthermia, susceptibility to, 5 Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV004178949.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023
Likely benign (Apr 11, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital myopathy 18 Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV004178951.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023
Likely benign (Apr 11, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypokalemic periodic paralysis, type 1 Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV004178952.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023
Likely Benign (Dec 18, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Malignant hyperthermia, susceptibility to, 5 (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004821513.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Number of individuals with the variant: 17
Likely benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005261072.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Likely benign (Jan 04, 2023)	no assertion criteria provided Method: clinical testing	CACNA1S-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004713383.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

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

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs550584336 ...

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 13, 2024

ClinVar Genomic variation as it relates to human health

NM_000069.3(CACNA1S):c.1935C>T (p.Phe645=)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs550584336 ...