NM_000069.3(CACNA1S):c.982C>A (p.Leu328Met) AND Thyrotoxic periodic paralysis, susceptibility to, 1

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Apr 11, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV003338729.4

Allele description [Variation Report for NM_000069.3(CACNA1S):c.982C>A (p.Leu328Met)]

NM_000069.3(CACNA1S):c.982C>A (p.Leu328Met)

Gene:

CACNA1S:calcium voltage-gated channel subunit alpha1 S [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q32.1

Genomic location:

Preferred name:

NM_000069.3(CACNA1S):c.982C>A (p.Leu328Met)

HGVS:

NC_000001.11:g.201087848G>T
NG_009816.2:g.29719C>A
NM_000069.3:c.982C>AMANE SELECT
NP_000060.2:p.Leu328Met
NC_000001.10:g.201056976G>T
NG_009816.1:g.29719C>A
NM_000069.2:c.982C>A

Protein change:

L328M

Links:

dbSNP: rs1558078309

NCBI 1000 Genomes Browser:

rs1558078309

Molecular consequence:

NM_000069.3:c.982C>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Thyrotoxic periodic paralysis, susceptibility to, 1 (TTPP1)
Identifiers:: MONDO: MONDO:0008570; MedGen: C2749982; Orphanet: 79102; OMIM: 188580

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004047467	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004179199	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Apr 11, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004047467

Neuberg Centre For Genomic Medicine, NCGM

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004179199

Genome-Nilou Lab

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Apr 11, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Neuberg Centre For Genomic Medicine, NCGM, SCV004047467.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

The missense variant in c.982C>A (p.Leu328Met) in CACNA1S gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Leu328Met variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Uncertain Significance. The amino acid Leu at position 328 is changed to a Met changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Leu328Met in CACNA1S is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as uncertain significance. This variant was identified in the proband in heterozygous state. This variant is also identified in asymptomatic mother, it is not likely to cause the disease.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome-Nilou Lab, SCV004179199.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Apr 6, 2024

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Relating variation to medicine