NM_001128840.3(CACNA1D):c.1220+678G>A AND Primary aldosteronism, seizures, and neurologic abnormalities

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Jan 14, 2015)

Review status:(0/4) 0 stars out of maximum of 4 stars

no assertion criteria provided

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000056307.29

Allele description [Variation Report for NM_001128840.3(CACNA1D):c.1220+678G>A]

NM_001128840.3(CACNA1D):c.1220+678G>A

Gene:
CACNA1D:calcium voltage-gated channel subunit alpha1 D [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
3p21.1
Genomic location:
Preferred name:
NM_001128840.3(CACNA1D):c.1220+678G>A
HGVS:
  • NC_000003.12:g.53673804G>A
  • NG_032999.1:g.183756G>A
  • NM_000720.4:c.1208G>A
  • NM_001128839.3:c.1220+678G>A
  • NM_001128840.3:c.1220+678G>AMANE SELECT
  • NP_000711.1:p.Gly403Asp
  • NC_000003.11:g.53707831G>A
  • NM_000720.2:c.1208G>A
  • NM_000720.3:c.1208G>A
Protein change:
G403D; GLY403ASP
Links:
OMIM: 114206.0002; dbSNP: rs386834264
NCBI 1000 Genomes Browser:
rs386834264
Molecular consequence:
  • NM_001128839.3:c.1220+678G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001128840.3:c.1220+678G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000720.4:c.1208G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Primary aldosteronism, seizures, and neurologic abnormalities (PASNA)
Identifiers:
MONDO: MONDO:0014200; MedGen: C3809609; Orphanet: 369929; OMIM: 615474

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000087476OMIMno assertion criteria providedPathogenic
(Sep 1, 2013)
germlineliterature only

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

SCV000238465Division of Human Genetics,Children's Hospital of Philadelphia - CSER-PediSeqno assertion criteria providedLikely pathogenic
(Jan 14, 2015)
de novoresearch

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only
not providedde novoyesnot providednot providednot providednot providednot providedresearch

Citations

PubMed

Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism.

Scholl UI, Goh G, Stölting G, de Oliveira RC, Choi M, Overton JD, Fonseca AL, Korah R, Starker LF, Kunstman JW, Prasad ML, Hartung EA, Mauras N, Benson MR, Brady T, Shapiro JR, Loring E, Nelson-Williams C, Libutti SK, Mane S, Hellman P, Westin G, et al.

Nat Genet. 2013 Sep;45(9):1050-4. doi: 10.1038/ng.2695. Epub 2013 Aug 4.

PubMed [citation]
PMID:
23913001
PMCID:
PMC3876926

Details of each submission

From OMIM, SCV000087476.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (1)

Description

In a 3-year-old girl of European ancestry with primary aldosteronism, seizures, and neurologic abnormalities (PASNA; 615474), Scholl et al. (2013) identified heterozygosity for a de novo c.1208G-A transition in exon 8B of the CACNA1D gene, resulting in a gly403-to-asp (G403D) substitution at a highly conserved residue within the S6 segments that line the channel pore. The mutation was not present in her unaffected parents and had not been reported in SNP or exome databases. Whole-cell patch-clamp recordings in HEK293 cells showed channel activation with the G403D mutant at less depolarized potentials than with wildtype, as well as impaired inactivation. In addition, increased current density with the G403D mutant was observed.

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

From Division of Human Genetics,Children's Hospital of Philadelphia - CSER-PediSeq, SCV000238465.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedresearch PubMed (1)

Description

The variant (c.1208G>A) is likely pathogenic because it was previously reported as a de novo alteration in a patient with primary aldosteronism, seizures, and global developmental delays (Scholl et al. 2013, PMID: 23913001). Electrophysiological study of this variant showed that it was comparable to a different mutation at amino acid position 403 (p.Gly403Arg) found in an adrenal aldosterone-producing adenoma that is activated at less depolarizing potentials and impairs the inactivation of the wildtype allele (Scholl et al. 2013, PMID: 23913001). This variant does not occur in ExAC 0.3 even though this genomic region is well-covered.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1de novoyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Aug 6, 2020

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