rs16969925

Positions:

chr19-35033545-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PP3PP5_Very_Strong

The NM_001037.5(SCN1B):c.254G>A(p.Arg85His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,908 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

SCN1B
NM_001037.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 3.50

Variant links:

Genes affected

SCN1B (HGNC:10586): (sodium voltage-gated channel beta subunit 1) Voltage-gated sodium channels are heteromeric proteins that function in the generation and propagation of action potentials in muscle and neuronal cells. They are composed of one alpha and two beta subunits, where the alpha subunit provides channel activity and the beta-1 subunit modulates the kinetics of channel inactivation. This gene encodes a sodium channel beta-1 subunit. Mutations in this gene result in generalized epilepsy with febrile seizures plus, Brugada syndrome 5, and defects in cardiac conduction. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Oct 2009]

SCN1B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM1

In a disulfide_bond (size 81) in uniprot entity SCN1B_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_001037.5

PP3

MetaRNN computational evidence supports a deleterious effect, 0.823

PP5

Variant 19-35033545-G-A is Pathogenic according to our data. Variant chr19-35033545-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 60767.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-35033545-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
SCN1B	NM_001037.5 linkuse as main transcript	c.254G>A	p.Arg85His	missense_variant	3/6	ENST00000262631.11	NP_001028.1
SCN1B	NM_199037.5 linkuse as main transcript	c.254G>A	p.Arg85His	missense_variant	3/3		NP_950238.1
SCN1B	NM_001321605.2 linkuse as main transcript	c.155G>A	p.Arg52His	missense_variant	3/6		NP_001308534.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN1B	ENST00000262631.11 linkuse as main transcript	c.254G>A	p.Arg85His	missense_variant	3/6	1	NM_001037.5	ENSP00000262631	P1	Q07699-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251350

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135838

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461814

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727190

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000224

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152094

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74284

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000474

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Brugada syndrome 5

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 26, 2024

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 85 of the SCN1B protein (p.Arg85His). This variant is present in population databases (rs16969925, gnomAD 0.008%). This missense change has been observed in individual(s) with clinical features of generalized epilepsy with febrile seizures plus (GEFS+) (PMID: 17020904). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 60767). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects SCN1B function (PMID: 17629415, 19808477). For these reasons, this variant has been classified as Pathogenic. -

Generalized epilepsy with febrile seizures plus, type 1;C2748541:Brugada syndrome 5;C3809311:Atrial fibrillation, familial, 13;C4479236:Developmental and epileptic encephalopathy, 52

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Atrial fibrillation, familial, 13

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2009

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 31, 2020

Identified in an individual with atrial fibrillation who had no neurological phenotype (Watanabe et al., 2009); Published functional studies demonstrate a damaging effect as this variant results in a loss-of-function of the resultant channel protein (Xu et al., 2007; Watanabe et al., 2009); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 17604911, 17629415, 19710327, 27216889, 17020904, 19808477, 23838598, 28717674, 31465153, 31980526) -

SCN1B-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 24, 2023

The SCN1B c.254G>A variant is predicted to result in the amino acid substitution p.Arg85His. This variant has been reported in the heterozygous state in at least two individuals with generalized epilepsy with febrile seizures plus (GEFS+) (Scheffer et al. 2007. PubMed ID: 17020904; Bayat et al. 2022. PubMed ID: 35723786) and one individual with atrial fibrillation and aortic stenosis without a history of seizures (Watanabe et al. 2009. PubMed ID: 19808477). It has also been reported in the homozygous state in an individual with Dravet syndrome (Ganapathy et al. 2019. PubMed ID: 31069529). Moreover, this variant was shown to strongly co-segregate with disease in at least one family (Scheffer et al. 2007. PubMed ID: 17020904) and reportedly arose de novo in another (Bayat et al. 2022. PubMed ID: 35723786). Multiple in vitro studies have demonstrated that this variant negatively impacts the ability of the SCN1B protein to modulate the function of sodium channel proteins expressed in brain and cardiac tissue (Xu et al. 2007. PubMed ID: 1762941; Watanabe et al. 2009. PubMed ID: 19808477) and disrupts SCN1B-mediated cell adhesion (Shimizu et al. 2016. PubMed ID: 27216889). This variant is reported in 0.0080% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-35524449-G-A). Of note, another missense variant at the same amino acid position (p.Arg85Cys) has been reported as pathogenic in GEFS+ patients with functional impacts similar to the p.Arg85His variant (Scheffer et al. 2007. PubMed ID: 17020904; Xu et al. 2007. PubMed ID: 17629415). Taken together, the p.Arg85His variant is interpreted as pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 09, 2023

The p.R85H variant (also known as c.254G>A), located in coding exon 3 of the SCN1B gene, results from a G to A substitution at nucleotide position 254. The arginine at codon 85 is replaced by histidine, an amino acid with highly similar properties. This variant has been reported in an individual with atrial fibrillation (Watanabe H et al. Circ Arrhythm Electrophysiol, 2009 Jun;2:268-75). This variant has also been reported in two families and multiple individuals with presentations ranging from isolated febrile seizures to generalized epilepsy febrile seizures plus (GEFS+) and cardiac anomalies (Scheffer IE et al. Brain, 2007 Jan;130:100-9; Huo YC et al. Proc Natl Acad Sci, 2020 Feb;117:3053-3062; personal communications). Additionally, this alteration was observed in the homozygous state in an individual with seizure phenotype; however, cardiac clinical information was not provided (Ganapathy A. et al. Neurol. 2019 Aug;266(8):1919-1926). Another variant affecting this codon (p.R85C, c.253C>T) has been reported in association with seizure phenotype (Scheffer IE et al. Brain, 2007 Jan;130:100-9). Functional studies have suggested this variant may impact sodium channel function; however, the physiological relevance of the reported findings is unclear (Xu R et al. Neuroscience, 2007 Aug;148:164-74; Watanabe H et al. Circ Arrhythm Electrophysiol. 2009 Jun;2(3):268-75; Patino GA et al. J Neurosci, 2011 Oct;31:14577-91; Shimizu H et al. Sci Rep, 2016 May;6:26618). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is likely pathogenic for autosomal dominant SCN1B-related epilepsy with febrile seizures; however, the association of this alteration with autosomal recessive early infantile epileptic encephalopathy and autosomal dominant Brugada syndrome is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.24

T;T;.;.;.

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Benign

0.74

LIST_S2

Uncertain

0.91

.;D;D;D;D

M_CAP

Uncertain

0.22

MetaRNN

Pathogenic

0.82

D;D;D;D;D

MetaSVM

Uncertain

0.72

MutationAssessor

Benign

1.7

L;L;L;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-2.1

N;.;N;.;.

REVEL

Pathogenic

0.72

Sift

Benign

0.051

T;.;D;.;.

Sift4G

Benign

0.18

T;.;T;.;.

Polyphen

0.99

D;D;D;.;.

Vest4

0.51

MutPred

0.81

Loss of stability (P = 0.0863);Loss of stability (P = 0.0863);Loss of stability (P = 0.0863);.;.;

MVP

0.99

MPC

1.8

ClinPred

0.69

GERP RS

3.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.14

gMVP

0.87

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over