19-13261526-C-T

Variant names:

• chr19-13261526-C-T
• rs794727411
• NM_001127222.2:c.4174G>A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_001127222.2(CACNA1A):​c.4174G>A​(p.Val1392Met) 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:23 O:1
• Conservation: PhyloP100: 7.88

Genes affected

CACNA1A (HGNC:1388): (calcium voltage-gated channel subunit alpha1 A) 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, alpha-1A, B, C, D, E, and S. This gene encodes the alpha-1A subunit, which is predominantly expressed in neuronal tissue. Mutations in this gene are associated with 2 neurologic disorders, familial hemiplegic migraine and episodic ataxia 2. This gene also exhibits polymorphic variation due to (CAG)n-repeats. Multiple transcript variants encoding different isoforms have been found for this gene. In one set of transcript variants, the (CAG)n-repeats occur in the 3' UTR, and are not associated with any disease. But in another set of variants, an insertion extends the coding region to include the (CAG)n-repeats which encode a polyglutamine tract. Expansion of the (CAG)n-repeats from the normal 4-18 to 21-33 in the coding region is associated with spinocerebellar ataxia 6. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM1: In a repeat III (size 283) in uniprot entity CAC1A_HUMAN there are 14 pathogenic changes around while only 1 benign (93%) in NM_001127222.2
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the CACNA1A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 137 curated pathogenic missense variants (we use a threshold of 10). The gene has 132 curated benign missense variants. Gene score misZ: 5.7845 (above the threshold of 3.09). Trascript score misZ: 3.9354 (above the threshold of 3.09). GenCC associations: The gene is linked to benign paroxysmal torticollis of infancy, developmental and epileptic encephalopathy, 42, undetermined early-onset epileptic encephalopathy, episodic ataxia type 2, familial or sporadic hemiplegic migraine, spinocerebellar ataxia type 6, Lennox-Gastaut syndrome, migraine, familial hemiplegic, 1.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.928
• PP5: Variant 19-13261526-C-T is Pathogenic according to our data. Variant chr19-13261526-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 195935.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13261526-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.4174G>A	p.Val1392Met	missense_variant	Exon 26 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.4174G>A	p.Val1392Met	missense_variant	Exon 26 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.4186G>A	p.Val1396Met	missense_variant	Exon 26 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.4180G>A	p.Val1394Met	missense_variant	Exon 26 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.4177G>A	p.Val1393Met	missense_variant	Exon 26 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.4177G>A	p.Val1393Met	missense_variant	Exon 26 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.4177G>A	p.Val1393Met	missense_variant	Exon 26 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.4036G>A	p.Val1346Met	missense_variant	Exon 25 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.4177G>A	p.Val1393Met	missense_variant	Exon 26 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.4186G>A	p.Val1396Met	missense_variant	Exon 26 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.4177G>A	p.Val1393Met	missense_variant	Exon 26 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.4180G>A	p.Val1394Met	missense_variant	Exon 26 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.4177G>A	p.Val1393Met	missense_variant	Exon 26 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.4177G>A	p.Val1393Met	missense_variant	Exon 26 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.4177G>A	p.Val1393Met	missense_variant	Exon 26 of 46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1448688 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 719322

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:23 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:6

Aug 31, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 20, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 25, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 29056246, 27959697, 28007337, 30283815, 31487502, 31468518, 29100083, 34489640, 33258288, 33425808, 34102571) -

May 20, 2019

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Developmental and epileptic encephalopathy, 42 Pathogenic:6

Dec 14, 2017

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jun 22, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed missense variant c.4174G>A(p.Val1392Met) in CACNA1A gene has been reported previously in heterozygous state in multiple individuals with epileptic encephalopathy and ataxia, tremor, developmental delay, and epilepsy (Costain G, et al., 2019, Balciuniene J, et al., 2019). Experimental studies have shown that this missense change affects CACNA1A function (Jiang X, et al., 2019). This variant is absent in gnomAD Exomes. It has been submitted to ClinVar as Likely Pathogenic/ Pathogenic (multiple submissions). The amino acid Val at position 1392 is changed to a Met changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence (SIFT-damaging and MutationTaster-disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid p.Val1392Met in CACNA1A is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

Jun 03, 2020

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Mar 05, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 20, 2022

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was identified as de novo (maternity and paternity confirmed)._x000D_ Criteria applied: PS2_VSTR, PS4, PM5_STR, PS3_MOD, PM2_SUP, PP2, PP3 -

Jan 03, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000195935, PS1_S). The variant has been previously reported as de novo in a similarly affected individual (PMID: 28007337, 29100083, PS2_S). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000280773,VCV001285568, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.889, PP3_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Episodic ataxia type 2 Pathogenic:2

Apr 25, 2021

Pediatrics, MediClubGeorgia

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has previously been described as disease causing for Ataxia, ClinVar lists this variant as pathogenic (Variation ID: 195935) and uncertain (Variation ID: 195935) and likely pathogenic (ID: 195935). This variant is absent parents. PolyPhen: Probably damaging ; Align-GVGD: C0; MutationTaster: Disease causing Conservation_nt: high; Conservation_aa: weak; This variant is absent in population databases. -

Mar 05, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Migraine, familial hemiplegic, 1 Pathogenic:2

May 07, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP3,PP4. -

Mar 05, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42 Pathogenic:1 Other:1

-

GenomeConnect - Invitae Patient Insights Network

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Pathogenic and reported on 12-31-2020 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Nov 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1393 of the CACNA1A protein (p.Val1393Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with epileptic encephalopathy and ataxia, tremor, developmental delay, and epilepsy (PMID: 28007337, 29056246, 29100083, 30283815). In at least one individual the variant was observed to be de novo. This variant is also known as NM_023035.2:c.4186G>A (p.V1396M). ClinVar contains an entry for this variant (Variation ID: 195935). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CACNA1A protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects CACNA1A function (PMID: 31468518). For these reasons, this variant has been classified as Pathogenic. -

Spinocerebellar ataxia type 6 Pathogenic:1

Mar 05, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Episodic ataxia type 2;C1832884:Migraine, familial hemiplegic, 1 Pathogenic:1

Oct 16, 2014

Baylor Genetics

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Our laboratory reported dual molecular diagnoses in CACNA1A (NM_001174080.1, c.4177G>A) and SLC26A1 (NM_022042.2, c.1487T>G) in one individual with reported features of intractable epilepsy, global developmental delay, tremor, ataxia, hyperlipidemia, growth hormone deficiency, and stable right optic nerve glioma. Missense and truncating variants in CACNA1A have been reported in patients with epilepsy (PMID:18940563;PMID:21703448) -

Inborn genetic diseases Pathogenic:1

Jun 04, 2020

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The alteration results in an amino acid change:_x000D_ _x000D_ The c.4177G>A (p.V1393M) alteration is located in coding exon 26 of the CACNA1A gene. This alteration results from a G to A substitution at nucleotide position 4177, causing the valine (V) at amino acid position 1393 to be replaced by a methionine (M). The alteration is not observed in population databases: _x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the CACNA1A c.4177G>A alteration was not observed, with coverage at this position. The alteration has been observed in affected individuals:_x000D_ _x000D_ The c.4177G>A (p.V1393M) alteration has been observed de novo in multiple unrelated affected patients. Common clinical features include seizures, ataxia, tremors, developmental delay, and intellectual disability (Travaglini, 2017; Butler, 2017; Cordeiro, 2018; Costain, 2019; Jiang, 2019). The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The p.V1393 amino acid is conserved in available vertebrate species. The amino acid is located in a functionally important protein domain:_x000D_ _x000D_ The p.V1393 amino acid is located in the S5 transmembrane segment of domain III of the Cav2.1 P/Q type voltage-dependent calcium channel. The S5 and S6 helices line the inner pore surface of the ion channel (Rajakulendran, 2012). Functional analysis reveals a damaging effect of the amino acid alteration: _x000D_ _x000D_ Functional analysis using whole cell voltage-clamp recordings of the mouse homologous variant in HEK293 cells demonstrated that the p.V1393M alteration increased peak density compared to wild type and altered current kinetics with a steeper activation curve and midpoint of activation that was more hyperpolarized. In addition, expression levels of mutant protein in the cell membrane was 50% of wild type expression levels (Jiang, 2019). The alteration is predicted deleterious by in silico modeling:_x000D_ _x000D_ The p.V1393M alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Migraine Pathogenic:1

Mar 05, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Spinocerebellar ataxia type 6;C1720416:Episodic ataxia type 2;C1832884:Migraine, familial hemiplegic, 1;C4479236:Developmental and epileptic encephalopathy, 52 Pathogenic:1

Mar 20, 2022

Wendy Chung Laboratory, Columbia University Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Spinocerebellar ataxia type 6;C1720416:Episodic ataxia type 2;C1832884:Migraine, familial hemiplegic, 1;C4310716:Developmental and epileptic encephalopathy, 42 Pathogenic:1

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PP3_Moderate+PP2+PM5+PS4_Moderate+PM6+PP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	.;.;T;.;.;.;.;.;.;T;.;.;.;T;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	.;.;.;.;H;.;.;.;.;.;.;.;H;.;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-2.7	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Pathogenic	0.0010	D;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.79
MutPred		0.73		.;.;Loss of catalytic residue at V1393 (P = 0.0413);Loss of catalytic residue at V1393 (P = 0.0413);Loss of catalytic residue at V1393 (P = 0.0413);.;Loss of catalytic residue at V1393 (P = 0.0413);.;.;Loss of catalytic residue at V1393 (P = 0.0413);Loss of catalytic residue at V1393 (P = 0.0413);.;Loss of catalytic residue at V1393 (P = 0.0413);.;Loss of catalytic residue at V1393 (P = 0.0413);
MVP		0.97
MPC		2.4
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.42
gMVP		0.95

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: rs794727411; hg19: chr19-13372340;