rs386834264

chr3-53673804-G-A

Variant summary

Our verdict is Pathogenic. Variant got 21 ACMG points: 21P and 0B. PS1_Moderate PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000720.4(CACNA1D):c.1208G>A(p.Gly403Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G403R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CACNA1D NM_000720.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 10.0

Genes affected

CACNA1D (HGNC:1391): (calcium voltage-gated channel subunit alpha1 D) Voltage-dependent calcium channels mediate the entry of calcium ions into excitable cells, and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, and gene expression. Calcium channels are multisubunit complexes composed of alpha-1, beta, alpha-2/delta, and gamma subunits. The channel activity is directed by the pore-forming alpha-1 subunit, whereas the others act as auxiliary subunits regulating this activity. The distinctive properties of the calcium channel types are related primarily to the expression of a variety of alpha-1 isoforms, namely alpha-1A, B, C, D, E, and S. This gene encodes the alpha-1D subunit. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2012]

ACMG classification

Verdict is Pathogenic. Variant got 21 ACMG points.

• PS1: Transcript NM_000720.4 (CACNA1D) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a transmembrane_region Helical; Name=S6 of repeat I (size 24) in uniprot entity CAC1D_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_000720.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-53673803-G-C is described in Lovd as [Pathogenic].
• PP2: Missense variant where missense usually causes diseases, CACNA1D
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973
• PP5: Variant 3-53673804-G-A is Pathogenic according to our data. Variant chr3-53673804-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 66072.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-53673804-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1D	NM_000720.4	c.1208G>A	p.Gly403Asp	missense_variant	8/49	ENST00000288139.11
CACNA1D	NM_001128840.3	c.1220+678G>A		intron_variant		ENST00000350061.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1D	ENST00000288139.11	c.1208G>A	p.Gly403Asp	missense_variant	8/49	1	NM_000720.4	P2
CACNA1D	ENST00000350061.11	c.1220+678G>A		intron_variant		1	NM_001128840.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Likely pathogenic, no assertion criteria provided	literature only	Richard Lifton Laboratory, Yale University School of Medicine	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 10, 2023	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 403 of the CACNA1D protein (p.Gly403Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with CACNA1D-related conditions (PMID: 23913001, 28318089). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 66072). 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 CACNA1D protein function. Experimental studies have shown that this missense change affects CACNA1D function (PMID: 23913001). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 10, 2020	This variant occurs de novo in this current individual and in published literature (PMID: 28318089, 23913001). Assessment of experimental evidence suggests this is gain-of-function variant (PMID: 23913001).This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org).This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study. -

Aldosterone-producing adenoma with seizures and neurological abnormalities Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2013	- -
Likely pathogenic, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Jan 14, 2015	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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
Cadd	Benign	22
Dann	Uncertain	1.0
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;.;D;D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D
MetaSVM	Pathogenic	0.85	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.97	D
Polyphen		1.0	.;.;D;D;.;.
Vest4		0.99
MutPred		0.87		.;Loss of catalytic residue at V404 (P = 0.0388);Loss of catalytic residue at V404 (P = 0.0388);Loss of catalytic residue at V404 (P = 0.0388);Loss of catalytic residue at V404 (P = 0.0388);.;
MVP		0.99
MPC		2.1
ClinPred		1.0	D
GERP RS		5.2
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs386834264; hg19: chr3-53707831;