NM_001127222.2(CACNA1A):c.4035_4043del (p.1346VLR[1]) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Aug 10, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV002811312.3

Allele description [Variation Report for NM_001127222.2(CACNA1A):c.4035_4043del (p.1346VLR[1])]

NM_001127222.2(CACNA1A):c.4035_4043del (p.1346VLR[1])

Gene:

CACNA1A:calcium voltage-gated channel subunit alpha1 A [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

19p13.13

Genomic location:

Preferred name:

NM_001127222.2(CACNA1A):c.4035_4043del (p.1346VLR[1])

HGVS:

NC_000019.10:g.13262786_13262794del
NG_011569.1:g.248673_248681del
NM_000068.4:c.4047_4055del
NM_001127221.1:c.4038_4046del
NM_001127221.2:c.4038_4046del
NM_001127222.2:c.4035_4043delMANE SELECT
NM_001174080.2:c.4038_4046del
NM_023035.3:c.4047_4055del
NP_000059.3:p.1350VLR[1]
NP_001120693.1:p.1347VLR[1]
NP_001120693.1:p.Val1350_Arg1352del
NP_001120694.1:p.1346VLR[1]
NP_001167551.1:p.1347VLR[1]
NP_075461.2:p.1350VLR[1]
LRG_7t1:c.4038_4046del
LRG_7:g.248673_248681del
NC_000019.9:g.13373594_13373602del
NC_000019.9:g.13373600_13373608del
NM_001127221.1:c.4032_4040delCCTCCGAGT

Molecular consequence:

NM_000068.4:c.4047_4055del - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001127221.2:c.4038_4046del - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001127222.2:c.4035_4043del - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001174080.2:c.4038_4046del - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_023035.3:c.4047_4055del - inframe_deletion - [Sequence Ontology: SO:0001822]

Condition(s)

Name:: Episodic ataxia type 2 (EA2)
Synonyms:: Episodic ataxia with nystagmus; Nystagmus-associated episodic ataxia; Cerebellopathy, hereditary paroxysmal; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007163; MedGen: C1720416; Orphanet: 97; OMIM: 108500

Name:: Developmental and epileptic encephalopathy, 42 (DEE42)
Synonyms:: Epileptic encephalopathy, early infantile, 42
Identifiers:: MONDO: MONDO:0014917; MedGen: C4310716; OMIM: 617106

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003210384	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 10, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 28007337, 29997391, 33425808, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003210384

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 10, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Missense mutations of CACNA1A are a frequent cause of autosomal dominant nonprogressive congenital ataxia.

Travaglini L, Nardella M, Bellacchio E, D'Amico A, Capuano A, Frusciante R, Di Capua M, Cusmai R, Barresi S, Morlino S, Fernández-Fernández JM, Trivisano M, Specchio N, Valeriani M, Vigevano F, Bertini E, Zanni G.

Eur J Paediatr Neurol. 2017 May;21(3):450-456. doi: 10.1016/j.ejpn.2016.11.005. Epub 2016 Nov 30.

PubMed [citation]

PMID:: 28007337

Exome sequencing in congenital ataxia identifies two new candidate genes and highlights a pathophysiological link between some congenital ataxias and early infantile epileptic encephalopathies.

Valence S, Cochet E, Rougeot C, Garel C, Chantot-Bastaraud S, Lainey E, Afenjar A, Barthez MA, Bednarek N, Doummar D, Faivre L, Goizet C, Haye D, Heron B, Kemlin I, Lacombe D, Milh M, Moutard ML, Riant F, Robin S, Roubertie A, Sarda P, et al.

Genet Med. 2019 Mar;21(3):553-563. doi: 10.1038/s41436-018-0089-2. Epub 2018 Jul 12.

PubMed [citation]

PMID:: 29997391

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003210384.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

For these reasons, this variant has been classified as Pathogenic. This variant, c.4038_4046del, results in the deletion of 3 amino acid(s) of the CACNA1A protein (p.Val1350_Arg1352del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CACNA1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 2003613). This variant disrupts a region of the CACNA1A protein in which other variant(s) (p.Arg1352Gln) have been determined to be pathogenic (PMID: 28007337, 29997391, 33425808). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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