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NM_001037.5(SCN1B):c.363C>G (p.Cys121Trp) AND not provided

Germline classification:
Pathogenic/Likely pathogenic (6 submissions)
Last evaluated:
May 24, 2023
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
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:
RCV000171041.28

Allele description [Variation Report for NM_001037.5(SCN1B):c.363C>G (p.Cys121Trp)]

NM_001037.5(SCN1B):c.363C>G (p.Cys121Trp)

Gene:
SCN1B:sodium voltage-gated channel beta subunit 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
19q13.11
Genomic location:
Preferred name:
NM_001037.5(SCN1B):c.363C>G (p.Cys121Trp)
Other names:
p.C121W:TGC>TGG
HGVS:
  • NC_000019.10:g.35033654C>G
  • NG_013359.1:g.7967C>G
  • NM_001037.5:c.363C>GMANE SELECT
  • NM_001321605.2:c.264C>G
  • NM_199037.5:c.363C>G
  • NP_001028.1:p.Cys121Trp
  • NP_001308534.1:p.Cys88Trp
  • NP_950238.1:p.Cys121Trp
  • LRG_420t1:c.363C>G
  • LRG_420:g.7967C>G
  • LRG_420p1:p.Cys121Trp
  • NC_000019.9:g.35524558C>G
  • NM_001037.3:c.363C>G
  • NM_001037.4:c.363C>G
  • NM_199037.3:c.363C>G
  • Q07699:p.Cys121Trp
Protein change:
C121W; CYS121TRP
Links:
UniProtKB: Q07699#VAR_010165; OMIM: 600235.0001; dbSNP: rs104894718
NCBI 1000 Genomes Browser:
rs104894718
Molecular consequence:
  • NM_001037.5:c.363C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001321605.2:c.264C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_199037.5:c.363C>G - missense variant - [Sequence Ontology: SO:0001583]
Observations:
5

Condition(s)

Synonyms:
none provided
Identifiers:
MedGen: C3661900

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000223605GeneDx
criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)
Pathogenic
(May 24, 2023)
germlineclinical testing

Citation Link,

SCV000280460Stanford Center for Inherited Cardiovascular Disease, Stanford University
no assertion criteria provided
Likely pathogenicgermlineclinical testing

SCV000340270Eurofins Ntd Llc (ga)
criteria provided, single submitter

(EGL Classification Definitions 2015)
Pathogenic
(Mar 29, 2016)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV000615050Athena Diagnostics
criteria provided, single submitter

(Athena Diagnostics Criteria)
Pathogenic
(Dec 31, 2016)
germlineclinical testing

PubMed (25)
[See all records that cite these PMIDs]

SCV002501571AiLife Diagnostics, AiLife Diagnostics
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Jun 28, 2021)
germlineclinical testing

PubMed (14)
[See all records that cite these PMIDs]

SCV003825468Revvity Omics, Revvity
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Aug 11, 2022)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes1not providednot providednot providednot providedclinical testing
not providedgermlinenot provided2not providednot providednot providednot providedclinical testing
not providedgermlineunknown2not providednot providednot providednot providedclinical testing

Citations

PubMed

Modulatory proteins can rescue a trafficking defective epileptogenic Nav1.1 Na+ channel mutant.

Rusconi R, Scalmani P, Cassulini RR, Giunti G, Gambardella A, Franceschetti S, Annesi G, Wanke E, Mantegazza M.

J Neurosci. 2007 Oct 10;27(41):11037-46.

PubMed [citation]
PMID:
17928445
PMCID:
PMC6672853

Augmented currents of an HCN2 variant in patients with febrile seizure syndromes.

Dibbens LM, Reid CA, Hodgson B, Thomas EA, Phillips AM, Gazina E, Cromer BA, Clarke AL, Baram TZ, Scheffer IE, Berkovic SF, Petrou S.

Ann Neurol. 2010 Apr;67(4):542-6. doi: 10.1002/ana.21909.

PubMed [citation]
PMID:
20437590
PMCID:
PMC3383007
See all PubMed Citations (30)

Details of each submission

From GeneDx, SCV000223605.20

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

Published functional studies demonstrate altered channel function (Wallace et al., 1998; Meadows et al., 2002; Barbieri et al., 2012; Egri et al., 2012; Baroni et al., 2013; Kruger et al., 2016); Reported previously in an individual with late onset episodic ataxia; segregation analysis not performed (Maksemous et al., 2020); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23584539, 9697698, 12011299, 27216889, 22425777, 11866477, 12486163, 22292491, 24065921, 23527921, 17020904, 28070485, 28488083, 28717674, 29056246, 29620010, 30921204, 29263209, 29992740, 29661262, 29307654, 29335582, 31709768, 31211177, 32303391, 33526774, 33301879, 33841294, 34583279, 31440721, 32466254, 36288729, 24623842, 27277800)

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Stanford Center for Inherited Cardiovascular Disease, Stanford University, SCV000280460.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided2not providednot providedclinical testingnot provided

Description

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Cys121Trp (c.363C>G) in SCN1B This variant has been described in association with generalized epilepsy with febrile seizures-plus (GEFS+) but has not been reported in association with familial cardiomyopathies. Wallace et al (1998) reported a large family with GEFS+ with linkage with a l od score of 3.85. They then identified the p.Cys121Trp variant in SCN1B at the linked locus and concluded it was the causative variant. Interestingly, a few children in the family who had febrile seizures did not have this variant. The authors considered these cases to be either phenocopies or genocopies. The same group reported another family with this variant, in which 13 of 14 family members studied with GEFS+ had the p.Cys121Trp variant (Wallace et al 2002). Four unaffected family members carried the variant and the penetrance was estimated at 76%. This family had a common haplotype with the previously reported family, suggesting they belong to the same kindred or there was a found effect. There is evidence that this variant leads to loss-of-function in terms of modulation of channel-gating kinetics (Wallace et al 1998; Tammaro et al 2002). The variant is expected to disrupt a putative disulfide bridge that normally maintains an extracellular immunoglobulin-like fold. Another group reported a family with febrile seizures-plus and early-onset absence epilepsy that had a different variant in SCN1B (Audenaert et al 2003). Five of six affected individuals had the IVS2-2A>C variant, which resulted in the use of an cryptic splice acceptor site and deletion of five amino acids. Variants in this gene are now thought to be a rare cause of GEFS+ (Wallace et al 2001, Wallace et al 2002, Audenaert et al 2003). Wallace et al (1998) did not observe the variant in 96 control individuals. It is not listed in dbSNP (as of March 3rd, 2011).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided2not providednot providednot provided

From Eurofins Ntd Llc (ga), SCV000340270.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided2not providednot providedclinical testing PubMed (3)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided2not providednot providednot provided

From Athena Diagnostics, SCV000615050.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (25)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From AiLife Diagnostics, AiLife Diagnostics, SCV002501571.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (14)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided1not providednot providednot provided

From Revvity Omics, Revvity, SCV003825468.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 10, 2024