NM_000719.7(CACNA1C):c.6011G>T (p.Gly2004Val) AND not specified

Germline classification:: Likely benign (1 submission)
Last evaluated:: Aug 17, 2020
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001255539.1

Allele description [Variation Report for NM_000719.7(CACNA1C):c.6011G>T (p.Gly2004Val)]

NM_000719.7(CACNA1C):c.6011G>T (p.Gly2004Val)

Genes:

CACNA1C-AS1:CACNA1C antisense RNA 1 [Gene - HGNC]
CACNA1C:calcium voltage-gated channel subunit alpha1 C [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

12p13.33

Genomic location:

Preferred name:

NM_000719.7(CACNA1C):c.6011G>T (p.Gly2004Val)

HGVS:

NC_000012.12:g.2688673G>T
NG_008801.2:g.722888G>T
NM_000719.7:c.6011G>TMANE SELECT
NM_001129827.2:c.6155G>T
NM_001129829.2:c.6134G>T
NM_001129830.3:c.6116G>T
NM_001129831.2:c.6095G>T
NM_001129832.2:c.6071G>T
NM_001129833.2:c.6068G>T
NM_001129834.2:c.6068G>T
NM_001129835.2:c.6068G>T
NM_001129836.2:c.6062G>T
NM_001129837.2:c.6035G>T
NM_001129838.2:c.6035G>T
NM_001129839.2:c.6029G>T
NM_001129840.2:c.6011G>T
NM_001129841.2:c.6011G>T
NM_001129842.2:c.6011G>T
NM_001129843.2:c.6011G>T
NM_001129844.2:c.6002G>T
NM_001129846.2:c.5978G>T
NM_001167623.2:c.6011G>T
NM_001167624.3:c.6116G>T
NM_001167625.2:c.6191G>T
NM_199460.4:c.6260G>T
NP_000710.5:p.Gly2004Val
NP_001123299.1:p.Gly2052Val
NP_001123301.1:p.Gly2045Val
NP_001123302.2:p.Gly2039Val
NP_001123303.1:p.Gly2032Val
NP_001123304.1:p.Gly2024Val
NP_001123305.1:p.Gly2023Val
NP_001123306.1:p.Gly2023Val
NP_001123307.1:p.Gly2023Val
NP_001123308.1:p.Gly2021Val
NP_001123309.1:p.Gly2012Val
NP_001123310.1:p.Gly2012Val
NP_001123311.1:p.Gly2010Val
NP_001123312.1:p.Gly2004Val
NP_001123313.1:p.Gly2004Val
NP_001123314.1:p.Gly2004Val
NP_001123315.1:p.Gly2004Val
NP_001123316.1:p.Gly2001Val
NP_001123318.1:p.Gly1993Val
NP_001161095.1:p.Gly2004Val
NP_001161096.2:p.Gly2039Val
NP_001161097.1:p.Gly2064Val
NP_955630.3:p.Gly2087Val
LRG_334t1:c.6011G>T
LRG_334:g.722888G>T
NC_000012.11:g.2797839G>T
NM_000719.6:c.6011G>T

Protein change:

G1993V

Links:

dbSNP: rs374991642

NCBI 1000 Genomes Browser:

rs374991642

Molecular consequence:

NM_000719.7:c.6011G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001129827.2:c.6155G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001129829.2:c.6134G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001129830.3:c.6116G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001129831.2:c.6095G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001129832.2:c.6071G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001129833.2:c.6068G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001129834.2:c.6068G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001129835.2:c.6068G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001129836.2:c.6062G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001129837.2:c.6035G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001129838.2:c.6035G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001129839.2:c.6029G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001129840.2:c.6011G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001129841.2:c.6011G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001129842.2:c.6011G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001129843.2:c.6011G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001129844.2:c.6002G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001129846.2:c.5978G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001167623.2:c.6011G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001167624.3:c.6116G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001167625.2:c.6191G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_199460.4:c.6260G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001432002	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely benign (Aug 17, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001432002

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely benign
(Aug 17, 2020)

germline

clinical testing

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

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Gain-of-function mutations in the calcium channel CACNA1C (Cav1.2) cause non-syndromic long-QT but not Timothy syndrome.

Wemhöner K, Friedrich C, Stallmeyer B, Coffey AJ, Grace A, Zumhagen S, Seebohm G, Ortiz-Bonnin B, Rinné S, Sachse FB, Schulze-Bahr E, Decher N.

J Mol Cell Cardiol. 2015 Mar;80:186-95. doi: 10.1016/j.yjmcc.2015.01.002. Epub 2015 Jan 26.

PubMed [citation]

PMID:: 25633834

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001432002.1

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

Description

Variant summary: CACNA1C c.6011G>T (p.Gly2004Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.7e-05 in 246344 control chromosomes, predominantly at a frequency of 0.00015 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 15 fold of the estimated maximal expected allele frequency for a pathogenic variant in CACNA1C causing Timothy Syndrome phenotype (1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.6011G>T in individuals affected with Timothy Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (2x) and likely benign (1x). Based on the evidence outlined above, the variant was classified as likely benign.

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

Last Updated: Sep 29, 2024

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