VCV000386521.40 - ClinVar

NM_001127222.2(CACNA1A):c.6125C>T (p.Thr2042Met)

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.

(8)

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.

Conflicting classifications of pathogenicity
Uncertain significance(5); Likely benign(3)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001127222.2(CACNA1A):c.6125C>T (p.Thr2042Met)

Variation ID: 386521 Accession: VCV000386521.40

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19p13.13 19: 13212448 (GRCh38) [ NCBI UCSC ] 19: 13323262 (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	Mar 8, 2017	Oct 20, 2024	Jan 4, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001127222.2:c.6125C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001120694.1:p.Thr2042Met	missense
NM_001127221.2:c.6128C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001120693.1:p.Thr2043Met	missense
NM_000068.4:c.6143C>T	NP_000059.3:p.Thr2048Met	missense
NM_001127222.1:c.6125C>T
NM_001174080.2:c.6134C>T	NP_001167551.1:p.Thr2045Met	missense
NM_023035.3:c.6143C>T	NP_075461.2:p.Thr2048Met	missense
NC_000019.10:g.13212448G>A
NC_000019.9:g.13323262G>A
NG_011569.1:g.299013C>T
LRG_7:g.299013C>T
LRG_7t1:c.6128C>T	LRG_7p1:p.Thr2043Met

... more HGVS ... less HGVS

Protein change

T2043M, T2048M, T2045M, T2042M

Other names

Canonical SPDI

NC_000019.10:13212447: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.

Exome Aggregation Consortium (ExAC) 0.00002

The Genome Aggregation Database (gnomAD) 0.00003

The Genome Aggregation Database (gnomAD), exomes 0.00004

Trans-Omics for Precision Medicine (TOPMed) 0.00004

Links

ClinGen: CA9239469 dbSNP: rs563345694 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.
CACNA1A		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	3495	3803

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.
Developmental and epileptic encephalopathy, 42 Episodic ataxia type 2	Likely benign (1)	criteria provided, single submitter	Jan 4, 2024	RCV000541910.9
not provided	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	Jun 18, 2021	RCV000710970.31
Abnormal brainstem MRI signal intensity Abnormal cerebral white matter morphology Abnormal thalamic MRI signal intensity Bone marrow hypocellularity Cerebral venous thrombosis Combined immunodeficiency Hypertonia Muscle weakness Myelitis Neurogenic bladder Spastic gait Spasticity	Uncertain significance (1)	criteria provided, single submitter	-	RCV000735340.3
Developmental and epileptic encephalopathy, 42 Episodic ataxia type 2 Migraine, familial hemiplegic, 1 Spinocerebellar ataxia type 6	Uncertain significance (1)	criteria provided, single submitter	Oct 31, 2018	RCV000764178.3
Inborn genetic diseases	Likely benign (1)	criteria provided, single submitter	Jan 17, 2019	RCV002356583.3
CACNA1A-related disorder	Uncertain significance (1)	criteria provided, single submitter	Dec 28, 2022	RCV003985342.1

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.
Uncertain significance (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Abnormal brainstem MRI signal intensity Abnormal thalamic MRI signal intensity Abnormal cerebral white matter morphology Bone marrow hypocellularity Cerebral venous thrombosis Combined immunodeficiency Hypertonia Muscle weakness Myelitis Neurogenic bladder Spastic gait Spasticity Affected status: yes Allele origin: germline	Center for Personalized Medicine, Children's Hospital Los Angeles Accession: SCV000854493.1 First in ClinVar: Dec 16, 2018 Last updated: Dec 16, 2018	Sex: female Ethnicity/Population group: Non-Hispanic
Uncertain significance (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Episodic ataxia type 2 Migraine, familial hemiplegic, 1 Spinocerebellar ataxia type 6 Developmental and epileptic encephalopathy, 42 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000895180.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Uncertain significance (Aug 27, 2018)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Athena Diagnostics Accession: SCV000841286.2 First in ClinVar: Oct 20, 2018 Last updated: Jan 18, 2020
Likely benign (Jun 18, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000528222.4 First in ClinVar: Mar 08, 2017 Last updated: Apr 17, 2019	Comment: In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our … (more) In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 30755392) (less)
Likely benign (Jan 04, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Developmental and epileptic encephalopathy, 42 Episodic ataxia type 2 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: SCV000656780.7 First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024	Publications: PubMed (1) PubMed: 28492532
Uncertain significance (Jun 01, 2018)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV000892545.28 First in ClinVar: Mar 31, 2019 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Uncertain significance (Dec 28, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	CACNA1A-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004107122.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The CACNA1A c.6125C>T variant is predicted to result in the amino acid substitution p.Thr2042Met. This variant was reported in an individual with cerebral white matter … (more) The CACNA1A c.6125C>T variant is predicted to result in the amino acid substitution p.Thr2042Met. This variant was reported in an individual with cerebral white matter abnormalities, cerebral venous thrombosis, myelitis, immunodeficiency, and spasticity (referred to as c.6128C>T, p.Thr2043Met in Supplemental Table 2, Ji et al. 2019. PubMed ID: 30755392). This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-13323262-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
Likely benign (Jan 17, 2019)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002656996.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Comment: This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more) This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)

Comment:

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 30755392)

Comment:

The CACNA1A c.6125C>T variant is predicted to result in the amino acid substitution p.Thr2042Met. This variant was reported in an individual with cerebral white matter abnormalities, cerebral venous thrombosis, myelitis, immunodeficiency, and spasticity (referred to as c.6128C>T, p.Thr2043Met in Supplemental Table 2, Ji et al. 2019. PubMed ID: 30755392). This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-13323262-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Comment:

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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 rs563345694 ...

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 Nov 03, 2024

ClinVar Genomic variation as it relates to human health

NM_001127222.2(CACNA1A):c.6125C>T (p.Thr2042Met)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs563345694 ...