NM_000719.7(CACNA1C):c.1553G>A (p.Arg518His) AND Long QT syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Oct 4, 2023
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:: RCV000631664.8

Allele description [Variation Report for NM_000719.7(CACNA1C):c.1553G>A (p.Arg518His)]

NM_000719.7(CACNA1C):c.1553G>A (p.Arg518His)

Gene:

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.1553G>A (p.Arg518His)

HGVS:

NC_000012.12:g.2566466G>A
NG_008801.2:g.600681G>A
NM_000719.7:c.1553G>AMANE SELECT
NM_001129827.2:c.1553G>A
NM_001129829.2:c.1553G>A
NM_001129830.3:c.1553G>A
NM_001129831.2:c.1553G>A
NM_001129832.2:c.1553G>A
NM_001129833.2:c.1553G>A
NM_001129834.2:c.1553G>A
NM_001129835.2:c.1553G>A
NM_001129836.2:c.1553G>A
NM_001129837.2:c.1553G>A
NM_001129838.2:c.1553G>A
NM_001129839.2:c.1553G>A
NM_001129840.2:c.1553G>A
NM_001129841.2:c.1553G>A
NM_001129842.2:c.1553G>A
NM_001129843.2:c.1553G>A
NM_001129844.2:c.1544G>A
NM_001129846.2:c.1553G>A
NM_001167623.2:c.1553G>A
NM_001167624.3:c.1553G>A
NM_001167625.2:c.1553G>A
NM_199460.4:c.1553G>A
NP_000710.5:p.Arg518His
NP_001123299.1:p.Arg518His
NP_001123301.1:p.Arg518His
NP_001123302.2:p.Arg518His
NP_001123303.1:p.Arg518His
NP_001123304.1:p.Arg518His
NP_001123305.1:p.Arg518His
NP_001123306.1:p.Arg518His
NP_001123307.1:p.Arg518His
NP_001123308.1:p.Arg518His
NP_001123309.1:p.Arg518His
NP_001123310.1:p.Arg518His
NP_001123311.1:p.Arg518His
NP_001123312.1:p.Arg518His
NP_001123313.1:p.Arg518His
NP_001123314.1:p.Arg518His
NP_001123315.1:p.Arg518His
NP_001123316.1:p.Arg515His
NP_001123318.1:p.Arg518His
NP_001161095.1:p.Arg518His
NP_001161096.2:p.Arg518His
NP_001161097.1:p.Arg518His
NP_955630.3:p.Arg518His
LRG_334t1:c.1553G>A
LRG_334t2:c.1553G>A
LRG_334:g.600681G>A
NC_000012.11:g.2675632G>A
NM_000719.6:c.1553G>A
NM_001129827.1:c.1553G>A
NM_001167624.2:c.1553G>A

Protein change:

R515H; ARG518HIS

Links:

OMIM: 114205.0017; dbSNP: rs1057517711

NCBI 1000 Genomes Browser:

rs1057517711

Molecular consequence:

NM_000719.7:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001129827.2:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001129829.2:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001129830.3:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001129831.2:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001129832.2:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001129833.2:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001129834.2:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001129835.2:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001129836.2:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001129837.2:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001129838.2:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001129839.2:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001129840.2:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001129841.2:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001129842.2:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001129843.2:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001129844.2:c.1544G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001129846.2:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001167623.2:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001167624.3:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001167625.2:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_199460.4:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Long QT syndrome (LQTS)
Identifiers:: MONDO: MONDO:0002442; MeSH: D008133; MedGen: C0023976

Recent activity

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RecName: Full=DCN1-like protein 3; Short=DCNL3; AltName: Full=DCUN1 domain-conta...
RecName: Full=DCN1-like protein 3; Short=DCNL3; AltName: Full=DCUN1 domain-containing protein 3; AltName: Full=Defective in cullin neddylation protein 1-like protein 3; AltName: Full=Squamous cell carcinoma-related oncogene 3
gi|74728175|sp|Q8IWE4.1|DCNL3_HUMAN

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000752747	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 4, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 30025578, 31408100, 32161207, 26253506, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000752747

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 4, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

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

Whole Genome Sequencing Improves Outcomes of Genetic Testing in Patients With Hypertrophic Cardiomyopathy.

Bagnall RD, Ingles J, Dinger ME, Cowley MJ, Ross SB, Minoche AE, Lal S, Turner C, Colley A, Rajagopalan S, Berman Y, Ronan A, Fatkin D, Semsarian C.

J Am Coll Cardiol. 2018 Jul 24;72(4):419-429. doi: 10.1016/j.jacc.2018.04.078.

PubMed [citation]

PMID:: 30025578

Type 8 long QT syndrome: pathogenic variants in CACNA1C-encoded Cav1.2 cluster in STAC protein binding site.

Mellor GJ, Panwar P, Lee AK, Steinberg C, Hathaway JA, Bartels K, Christian S, Balaji S, Roberts JD, Simpson CS, Boczek NJ, Tester DJ, Radbill AE, Mok NS, Hamilton RM, Kaufman ES, Eugenio PL, Weiss R, January C, McDaniel GM, Leather RA, Erickson C, et al.

Europace. 2019 Nov 1;21(11):1725-1732. doi: 10.1093/europace/euz215.

PubMed [citation]

PMID:: 31408100

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000752747.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 518 of the CACNA1C protein (p.Arg518His). This variant is present in population databases (no rsID available, gnomAD 0.3%). This missense change has been observed in individuals with long QT syndrome or a complex phenotype of long QT syndrome and hypertrophic cardiomyopathy (PMID: 26253506, 30025578, 31408100, 32161207). ClinVar contains an entry for this variant (Variation ID: 372313). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CACNA1C protein function. Experimental studies have shown that this missense change affects CACNA1C function (PMID: 26253506). This variant disrupts the p.Arg518 amino acid residue in CACNA1C. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26253506; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

#	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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