19-35030821-A-C

Position:

• chr19-35030821-A-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PS1_Moderate PM2

The NM_001037.5(SCN1B):​c.1A>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000108 in 927,680 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000011 (0 hom.)
• Consequence: SCN1B NM_001037.5 start_lost
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3
• Conservation: PhyloP100: 0.694

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 12 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_001037.5 (SCN1B) was described as [Conflicting_classifications_of_pathogenicity] in ClinVar as 1040220
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN1B	NM_001037.5	c.1A>C	p.Met1?	start_lost	1/6	ENST00000262631.11
SCN1B	NM_199037.5	c.1A>C	p.Met1?	start_lost	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN1B	ENST00000262631.11	c.1A>C	p.Met1?	start_lost	1/6	1	NM_001037.5	P1
SCN1B	ENST00000415950.5	c.1A>C	p.Met1?	start_lost	1/3	1
SCN1B	ENST00000638536.1	c.1A>C	p.Met1?	start_lost	1/5	1		P1
SCN1B	ENST00000595652.5	c.1A>C	p.Met1?	start_lost	1/6	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000108 AC: 1 AN: 927680 Hom.: 0 Cov.: 13 AF XY: 0.00 AC XY: 0 AN XY: 453830

Gnomad4 AFR exome AF: 0.0000583

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Brugada syndrome 5 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 13, 2023

This sequence change affects the initiator methionine of the SCN1B mRNA. The next in-frame methionine is located at codon 34. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individuals with clinical features of autosomal dominant SCN1B-related conditions (PMID: 30660056; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 489074). For these reasons, this variant has been classified as Pathogenic. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 03, 2024

Variant summary: SCN1B c.1A>C (p.Met1Leu) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. Two of three in-silico tools predict a benign effect of the variant on protein function. The next downstream in-frame ATG start site is at codon 34 (Exon 2). Other initiation codon variants, as well as variants downstream of the initiation codon variant but upstream of the potential new start codon have been reported in association with SCN1B-related disorders in HGMD, but have not been reported as pathogenic by our lab or in ClinVar. The variant allele was found at a frequency of 1.1e-06 in 927680 control chromosomes (gnomAD v4). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1A>C in individuals affected with SCN1B-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. Three submitters have reported clinical-significance assessments for this variant to ClinVar after 2014 with conflicting interpretations (VUS, n = 2; likely pathogenic, n = 1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 13, 2023

Initiation codon variant in a gene for which loss-of-function is not a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 24069305, 30660056) -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 10, 2023

The p.M1? variant (also known as c.1A>C) is located in coding exon 1 of the SCN1B gene, results from an A to C substitution at nucleotide position 1. This alters the methionine residue at the initiation codon (ATG). This variant has been identified in a family with genetic epilepsy with febrile seizures plus (GEFS+); however, not all individuals with seizures tested positive for this variant (Myers KA et al. Epilepsy Res., 2019 02;150:66-69). This amino acid position is conserved on limited sequence alignment. Variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame; however, there is an in-frame methionine 34 amino acids from the initiation site, which may result in N-terminal truncation of unknown functional significance. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.16
CADD	Benign	18
DANN	Benign	0.81
DEOGEN2	Benign	0.12	T;T;.;.
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.32	N
LIST_S2	Uncertain	0.90	.;D;D;D
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.94	D;D;D;D
MetaSVM	Uncertain	-0.25	T
MutationTaster	Benign	1.0	D;D
PROVEAN	Benign	-0.93	N;.;N;.
REVEL	Uncertain	0.50
Sift	Benign	0.29	T;.;D;.
Sift4G	Pathogenic	0.0	D;.;D;D
Polyphen		0.0	B;B;B;B
Vest4		0.27
MutPred		0.88		Loss of catalytic residue at M1 (P = 0.0236);Loss of catalytic residue at M1 (P = 0.0236);Loss of catalytic residue at M1 (P = 0.0236);Loss of catalytic residue at M1 (P = 0.0236);
MVP		0.86
ClinPred		0.64	D
GERP RS		0.26
Varity_R		0.33
gMVP		0.79

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: rs1375857363; hg19: chr19-35521725;