rs386834264

Variant names:

• chr3-53673804-G-A
• rs386834264
• NM_000720.4:c.1208G>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 the same amino acid substitution has been previously reported as Likely pathogenic in 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 7 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 in the CACNA1D gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 11 curated pathogenic missense variants (we use a threshold of 10). The gene has 27 curated benign missense variants. Gene score misZ: 4.5817 (above the threshold of 3.09). Trascript score misZ: 6.6047 (above the threshold of 3.09). GenCC associations: The gene is linked to sinoatrial node dysfunction and deafness, aldosterone-producing adenoma with seizures and neurological abnormalities.
• 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 rank	MANE	Protein	UniProt
CACNA1D	NM_000720.4	c.1208G>A	p.Gly403Asp	missense_variant	Exon 8 of 49	ENST00000288139.11	NP_000711.1
CACNA1D	NM_001128840.3	c.1220+678G>A		intron_variant	Intron 8 of 47	ENST00000350061.11	NP_001122312.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1D	ENST00000288139.11	c.1208G>A	p.Gly403Asp	missense_variant	Exon 8 of 49	1	NM_000720.4	ENSP00000288139.3
CACNA1D	ENST00000350061.11	c.1220+678G>A		intron_variant	Intron 8 of 47	1	NM_001128840.3	ENSP00000288133.5

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

-

Richard Lifton Laboratory, Yale University School of Medicine

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jun 10, 2020

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Aug 10, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. For these reasons, this variant has been classified as Pathogenic. 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). -

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

Jan 14, 2015

Division of Human Genetics, Children's Hospital of Philadelphia

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

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. -

Sep 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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
PrimateAI	Pathogenic	0.97	D
PROVEAN	Pathogenic	-6.3	.;.;.;D;.;.
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	.;.;.;D;.;.
Sift4G	Pathogenic	0.0	.;.;.;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;