Congenital hyperinsulinism
Gene: CACNA1C

CACNA1C (calcium voltage-gated channel subunit alpha1 C)
EnsemblGeneIds (GRCh38): ENSG00000151067
EnsemblGeneIds (GRCh37): ENSG00000151067
OMIM: 114205, Gene2Phenotype
CACNA1C is in 10 panels

3 reviews

Arina Puzriakova (Genomics England Curator)

Green List (high evidence)

The rating of this gene has been updated to Green and the mode of inheritance set to 'MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown' following NHS Genomic Medicine Service approval.
Created: 31 Jan 2023, 4:38 p.m. | Last Modified: 31 Jan 2023, 4:38 p.m.

Panel Version: 2.32

Created: 31 Jan 2023, 4:38 p.m.
Last Modified: 31 Jan 2023, 4:38 p.m.
Panel version: 2.32

Sarah Leigh (Genomics England Curator)

Green List (high evidence)

Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Created: 27 Sep 2022, 11:42 a.m. | Last Modified: 27 Sep 2022, 11:42 a.m.

Panel Version: 2.21

Associated with in OMIM and as definitive Gen2Phen gene for Timothy syndrome (OMIM:601005). At least two CACNA1C variants have been reported in numerous cases of Timothy syndrome.
PMID: 35897673 reports novel heterozygous CACNA1C variant in a patient with congenital hyperinsulinism (CHI), which appears to have gain-of-function and loss-of-function effects at the electrophysiological level, explaining the hyperinsulinism and resulting hypoglycemia in the patient reported. It appeared that c.1679T>C, p.L566P (NM_000719.6) reported in this patient has a minor effects on the cardiac action potential in an in silico model, in contrast to c.1216G>T, p.G406R (NM_000719.6) which is associated with the Long QT in Timothy syndrome (OMIM:601005). Therefore the authors conclude that this represents a novel congeital non-syndromic hyperinsulinism.
Hypoglycemia is also seen in Timothy syndrome patients with c.1216G>T, p.G406R (Table S3, PMID: 35897673), it would therefore be appropriate to screen other patients with hyperinsulinism / hypoglycemia for CACNA1C variants.
Created: 27 Sep 2022, 11:41 a.m. | Last Modified: 27 Sep 2022, 11:41 a.m.

Panel Version: 2.20

Comment on mode of pathogenicity: In vitro studies show that c.1679T>C, p.Leu566Pro (NM_000719.6) appears to have loss-of-function effects by altering current amplitudes in mutant channels and a gain-of-function effect by slowing the voltage-dependent inactivation (PMID: 35897673).
Created: 27 Sep 2022, 10:36 a.m. | Last Modified: 27 Sep 2022, 10:36 a.m.

Panel Version: 2.19

Created: 27 Sep 2022, 10:36 a.m.
Last Modified: 27 Sep 2022, 10:36 a.m.
Panel version: 2.20

Eleanor Williams (Genomics England Curator)

Review on behalf of Sophie Muir from the Timothy Syndrome Alliance (TSA). Kummer S, Rinn S, Seemann G, Bachmann N, Timothy K, Thornton PS, Pillekamp F, Mayatepek E, Bergmann C, Meissner T, Decher N. Hyperinsulinemic Hypoglycemia Associated with a CaV1.2 Variant with Mixed Gain- and Loss-of-Function Effects.International Journal of Molecular Sciences. 2022; 23(15):8097. https://doi.org/10.3390/ijms23158097.
Created: 14 Sep 2022, 4:39 p.m. | Last Modified: 14 Sep 2022, 4:39 p.m.

Panel Version: 2.12

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Publications

35897673

Created: 14 Sep 2022, 4:39 p.m.
Last Modified: 14 Sep 2022, 4:39 p.m.
Panel version: 2.12

Details

Mode of Inheritance

MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Sources

NHS GMS
Expert Review Green
Expert review

Phenotypes

non-syndromic congeital hyperinsulinism
Timothy syndrome, OMIM:601005
Timothy syndrome, MONDO:0010979
CACNA1C-related disorder

OMIM

114205

Clinvar variants

Variants in CACNA1C

Penetrance

None

Publications

35897673

Mode of Pathogenicity

Other

Panels with this gene

History Filter Activity

15 Feb 2023, Gel status: 3

Set Phenotypes

Eleanor Williams (Genomics England Curator)

Phenotypes for gene: CACNA1C were changed from non-syndromic congeital hyperinsulinism; Timothy syndrome, OMIM:601005; Timothy syndrome, MONDO:0010979 to non-syndromic congeital hyperinsulinism; Timothy syndrome, OMIM:601005; Timothy syndrome, MONDO:0010979; CACNA1C-related disorder

31 Jan 2023, Gel status: 3

Removed Tag, Removed Tag, Removed Tag

Arina Puzriakova (Genomics England Curator)

Tag Q3_22_rating was removed from gene: CACNA1C. Tag Q3_22_MOI was removed from gene: CACNA1C. Tag Q3_22_NHS_review was removed from gene: CACNA1C.

31 Jan 2023, Gel status: 3

Added New Source, Added New Source, Status Update

Arina Puzriakova (Genomics England Curator)

Source Expert Review Green was added to CACNA1C. Source NHS GMS was added to CACNA1C. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)

27 Sep 2022, Gel status: 2