NM_001037.5:c.253C>T

Variant names:

• chr19-35033544-C-T
• rs786205830
• NM_001037.5:c.253C>T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM5 PP3_Strong PP5_Very_Strong

The NM_001037.5(SCN1B):​c.253C>T​(p.Arg85Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,806 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R85H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: SCN1B NM_001037.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 2.09

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-35033545-G-A is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.961
• PP5: Variant 19-35033544-C-T is Pathogenic according to our data. Variant chr19-35033544-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 190859.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN1B	NM_001037.5	c.253C>T	p.Arg85Cys	missense_variant	Exon 3 of 6	ENST00000262631.11	NP_001028.1
SCN1B	NM_199037.5	c.253C>T	p.Arg85Cys	missense_variant	Exon 3 of 3		NP_950238.1
SCN1B	NM_001321605.2	c.154C>T	p.Arg52Cys	missense_variant	Exon 3 of 6		NP_001308534.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN1B	ENST00000262631.11	c.253C>T	p.Arg85Cys	missense_variant	Exon 3 of 6	1	NM_001037.5	ENSP00000262631.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461806 Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 4 AN XY: 727188

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: 0.00000719

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Brugada syndrome 5 Pathogenic:1

Dec 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 85 of the SCN1B protein (p.Arg85Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant generalized epilepsy with febrile seizures plus (GEFS+) and autosomal recessive epileptic encephalopathy with cerebellar atrophy (PMID: 17020904, 31709768; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 190859). 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, 31709768). This variant disrupts the p.Arg85 amino acid residue in SCN1B. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17020904, 17629415, 19808477). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Developmental and epileptic encephalopathy, 52 Pathogenic:1

Feb 14, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense c.253C>T(p.Arg85Cys) variant in SCN1B gene has been reported in heterozygous state in multiple individuals affected with SCN1B related disorders (Aeby A, et. al., 2019). Experimental studies have shown that this missense change affects SCN1B function (Xu R, et. al., 2007). The p.Arg85Cys variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Uncertain Significance/Pathogenic/Likely pathogenic. The amino acid change p.Arg85Cys in SCN1B is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 85 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Likely Pathogenic. -

not provided Pathogenic:1

Sep 22, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Generalized epilepsy with febrile seizures plus, type 1 Pathogenic:1

Dec 20, 2016

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Pathogenic:1

Oct 31, 2022

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R85C variant (also known as c.253C>T), located in coding exon 3 of the SCN1B gene, results from a C to T substitution at nucleotide position 253. The arginine at codon 85 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been reported to segregate with disease in a family with multiple individuals across generations affected with seizure disorders, ranging from isolated febrile seizures through generalized epilepsy with febrile seizures plus (GEFS+); however, no cardiac clinical information was provided (Scheffer IE et al. Brain, 2007 Jan;130:100-9). This variant has been reported to segregate with disease in a second family with multiple heterozygous individuals affected with febrile seizures and one homozygous individual affected with an early infantile developmental and epileptic encephalopathy (EIDEE) and no detected cardiac arrhythmias (Aeby A et al. Ann Clin Transl Neurol, 2019 12;6:2354-2367). Functional studies have demonstrated that this variant, as well as close match p.R85H, fails to properly regulate the electrophysiological properties of sodium channels (Xu R et al. Neuroscience, 2007 Aug;148:164-74). This amino acid position is highly 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	0.94
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.57	D;D;.;.;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.94	.;D;D;D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Benign	1.7	L;L;L;.;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-4.2	D;.;D;.;.
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0080	D;.;D;.;.
Sift4G	Uncertain	0.040	D;.;D;.;.
Polyphen		1.0	D;D;D;.;.
Vest4		0.69
MutPred		0.87		Loss of disorder (P = 0.0163);Loss of disorder (P = 0.0163);Loss of disorder (P = 0.0163);.;.;
MVP		0.97
MPC		1.9
ClinPred		0.97	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.31
gMVP		0.94

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: rs786205830; hg19: chr19-35524448; COSMIC: COSV99386630; COSMIC: COSV99386630;