NM_001330260.2(SCN8A):c.3113A>G (p.Tyr1038Cys) AND Cognitive impairment with or without cerebellar ataxia

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jul 16, 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:: RCV002470618.2

Allele description [Variation Report for NM_001330260.2(SCN8A):c.3113A>G (p.Tyr1038Cys)]

NM_001330260.2(SCN8A):c.3113A>G (p.Tyr1038Cys)

Gene:

SCN8A:sodium voltage-gated channel alpha subunit 8 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

12q13.13

Genomic location:

Preferred name:

NM_001330260.2(SCN8A):c.3113A>G (p.Tyr1038Cys)

HGVS:

NC_000012.12:g.51769076A>G
NG_021180.3:g.184119A>G
NM_001177984.3:c.3113A>G
NM_001330260.1:c.3113A>G
NM_001330260.2:c.3113A>GMANE SELECT
NM_001369788.1:c.3113A>G
NM_014191.4:c.3113A>G
NP_001171455.1:p.Tyr1038Cys
NP_001317189.1:p.Tyr1038Cys
NP_001356717.1:p.Tyr1038Cys
NP_055006.1:p.Tyr1038Cys
LRG_1389t1:c.3113A>G
LRG_1389t2:c.3113A>G
LRG_1389:g.184119A>G
LRG_1389p1:p.Tyr1038Cys
LRG_1389p2:p.Tyr1038Cys
NC_000012.11:g.52162860A>G
NM_014191.3:c.3113A>G

Protein change:

Y1038C

Molecular consequence:

NM_001177984.3:c.3113A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001330260.2:c.3113A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369788.1:c.3113A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_014191.4:c.3113A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cognitive impairment with or without cerebellar ataxia (CIAT)
Identifiers:: MONDO: MONDO:0013680; MedGen: C3280415; OMIM: 614306

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002768844	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jul 16, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 31904124, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002768844

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jul 16, 2023)

germline

clinical testing

PubMed (2)
[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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Phenotypic and genetic spectrum of SCN8A-related disorders, treatment options, and outcomes.

Gardella E, Møller RS.

Epilepsia. 2019 Dec;60 Suppl 3:S77-S85. doi: 10.1111/epi.16319.

PubMed [citation]

PMID:: 31904124

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002768844.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene, and are associated with cognitive impairment with or without cerebellar ataxia (MIM#614306), and developmental and epileptic encephalopathy 13 (MIM#614558), respectively. In addition, gain of function is speculated for benign familial infantile seizures, 5 (MIM#617080) (PMID: 31904124, OMIM). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from tyrosine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated Na_trans_assoc domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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

Last Updated: Aug 4, 2024

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