NM_000719.7(CACNA1C):c.2570C>T (p.Pro857Leu) AND Long QT syndrome

Clinical significance:Conflicting interpretations of pathogenicity, Likely pathogenic(1);Uncertain significance(1) (Last evaluated: Dec 27, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000208178.2

Allele description [Variation Report for NM_000719.7(CACNA1C):c.2570C>T (p.Pro857Leu)]

NM_000719.7(CACNA1C):c.2570C>T (p.Pro857Leu)

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.2570C>T (p.Pro857Leu)
HGVS:
  • NC_000012.12:g.2593252C>T
  • NG_008801.2:g.627467C>T
  • NM_000719.7:c.2570C>TMANE SELECT
  • NM_001129827.2:c.2570C>T
  • NM_001129829.1:c.2570C>T
  • NM_001129830.3:c.2570C>T
  • NM_001129831.1:c.2570C>T
  • NM_001129832.1:c.2570C>T
  • NM_001129833.1:c.2570C>T
  • NM_001129834.1:c.2570C>T
  • NM_001129835.1:c.2570C>T
  • NM_001129836.1:c.2570C>T
  • NM_001129837.1:c.2570C>T
  • NM_001129838.1:c.2570C>T
  • NM_001129839.1:c.2570C>T
  • NM_001129840.2:c.2570C>T
  • NM_001129841.1:c.2570C>T
  • NM_001129842.1:c.2570C>T
  • NM_001129843.1:c.2570C>T
  • NM_001129844.1:c.2561C>T
  • NM_001129846.1:c.2570C>T
  • NM_001167623.2:c.2570C>T
  • NM_001167624.2:c.2570C>T
  • NM_001167625.1:c.2570C>T
  • NM_199460.3:c.2570C>T
  • NP_000710.5:p.Pro857Leu
  • NP_001123299.1:p.Pro857Leu
  • NP_001123301.1:p.Pro857Leu
  • NP_001123302.2:p.Pro857Leu
  • NP_001123303.1:p.Pro857Leu
  • NP_001123304.1:p.Pro857Leu
  • NP_001123305.1:p.Pro857Leu
  • NP_001123306.1:p.Pro857Leu
  • NP_001123307.1:p.Pro857Leu
  • NP_001123308.1:p.Pro857Leu
  • NP_001123309.1:p.Pro857Leu
  • NP_001123310.1:p.Pro857Leu
  • NP_001123311.1:p.Pro857Leu
  • NP_001123312.1:p.Pro857Leu
  • NP_001123313.1:p.Pro857Leu
  • NP_001123314.1:p.Pro857Leu
  • NP_001123315.1:p.Pro857Leu
  • NP_001123316.1:p.Pro854Leu
  • NP_001123318.1:p.Pro857Leu
  • NP_001161095.1:p.Pro857Leu
  • NP_001161096.2:p.Pro857Leu
  • NP_001161097.1:p.Pro857Leu
  • NP_955630.3:p.Pro857Leu
  • LRG_334t1:c.2570C>T
  • LRG_334:g.627467C>T
  • NC_000012.11:g.2702418C>T
  • NM_000719.6:c.2570C>T
Protein change:
P854L; PRO857LEU
Links:
OMIM: 114205.0006; dbSNP: rs750835733
NCBI 1000 Genomes Browser:
rs750835733
Molecular consequence:
  • NM_000719.7:c.2570C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129827.2:c.2570C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129829.1:c.2570C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129830.3:c.2570C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129831.1:c.2570C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129832.1:c.2570C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129833.1:c.2570C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129834.1:c.2570C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129835.1:c.2570C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129836.1:c.2570C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129837.1:c.2570C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129838.1:c.2570C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129839.1:c.2570C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129840.2:c.2570C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129841.1:c.2570C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129842.1:c.2570C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129843.1:c.2570C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129844.1:c.2561C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129846.1:c.2570C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001167623.2:c.2570C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001167624.2:c.2570C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001167625.1:c.2570C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_199460.3:c.2570C>T - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Name:
Long QT syndrome (LQTS)
Identifiers:
MONDO: MONDO:0002442; MeSH: D008133; MedGen: C0023976; OMIM: PS192500

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000263797Blueprint Geneticscriteria provided, single submitter
Likely pathogenic
(Jul 8, 2015)
germlineclinical testing

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

Citation Link,

SCV001226554Invitaecriteria provided, single submitter
Uncertain significance
(Dec 27, 2019)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes1not providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Genetic Testing in the Evaluation of Unexplained Cardiac Arrest: From the CASPER (Cardiac Arrest Survivors With Preserved Ejection Fraction Registry).

Mellor G, Laksman ZWM, Tadros R, Roberts JD, Gerull B, Simpson CS, Klein GJ, Champagne J, Talajic M, Gardner M, Steinberg C, Arbour L, Birnie DH, Angaran P, Leather R, Sanatani S, Chauhan VS, Seifer C, Healey JS, Krahn AD.

Circ Cardiovasc Genet. 2017 Jun;10(3). doi:pii: e001686. 10.1161/CIRCGENETICS.116.001686.

PubMed [citation]
PMID:
28600387

Exome sequencing and systems biology converge to identify novel mutations in the L-type calcium channel, CACNA1C, linked to autosomal dominant long QT syndrome.

Boczek NJ, Best JM, Tester DJ, Giudicessi JR, Middha S, Evans JM, Kamp TJ, Ackerman MJ.

Circ Cardiovasc Genet. 2013 Jun;6(3):279-89.

PubMed [citation]
PMID:
23677916
PMCID:
PMC3760222
See all PubMed Citations (3)

Details of each submission

From Blueprint Genetics, SCV000263797.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided1not providednot providednot provided

From Invitae, SCV001226554.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This sequence change replaces proline with leucine at codon 857 of the CACNA1C protein (p.Pro857Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with long QT syndrome (PMID: 23677916, 28600387, Invitae). ClinVar contains an entry for this variant (Variation ID: 222515). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). This variant disrupts the p.Pro857 amino acid residue in CACNA1C. Other variant(s) that disrupt this residue have been observed in individuals with CACNA1C-related conditions (PMID: 23677916), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 7, 2021

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