rs121918801

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM5PP2PP3_ModeratePP5

The NM_001165963.4(SCN1A):c.3925C>T(p.Leu1309Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000056 in 1,607,184 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1309H) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

SCN1A
NM_001165963.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1O:1

Conservation

PhyloP100: 7.93

Variant links:

Genes affected

SCN1A (HGNC:10585): (sodium voltage-gated channel alpha subunit 1) Voltage-dependent sodium channels are heteromeric complexes that regulate sodium exchange between intracellular and extracellular spaces and are essential for the generation and propagation of action potentials in muscle cells and neurons. Each sodium channel is composed of a large pore-forming, glycosylated alpha subunit and two smaller beta subunits. This gene encodes a sodium channel alpha subunit, which has four homologous domains, each of which contains six transmembrane regions. Allelic variants of this gene are associated with generalized epilepsy with febrile seizures and epileptic encephalopathy. Alternative splicing results in multiple transcript variants. The RefSeq Project has decided to create four representative RefSeq records. Three of the transcript variants are supported by experimental evidence and the fourth contains alternate 5' untranslated exons, the exact combination of which have not been experimentally confirmed for the full-length transcript. [provided by RefSeq, Oct 2015]

SCN1A links:

SCN1A-AS1 (HGNC:54069): (SCN1A and SCN9A antisense RNA 1)

SCN1A-AS1 links:

LOC102724058 (HGNC:):

LOC102724058 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 7 uncertain in NM_001165963.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-166009795-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 838026.Status of the report is criteria_provided_single_submitter, 1 stars.

PP2

Missense variant where missense usually causes diseases, SCN1A

PP3

MetaRNN computational evidence supports a deleterious effect, 0.885

PP5

Variant 2-166009796-G-A is Pathogenic according to our data. Variant chr2-166009796-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 68625.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, not_provided=1, Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN1A	NM_001165963.4 linkuse as main transcript	c.3925C>T	p.Leu1309Phe	missense_variant	23/29	ENST00000674923.1
LOC102724058	NR_110598.1 linkuse as main transcript	n.176-5817G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN1A	ENST00000674923.1 linkuse as main transcript	c.3925C>T	p.Leu1309Phe	missense_variant	23/29		NM_001165963.4	P4	P35498-1
SCN1A-AS1	ENST00000651574.1 linkuse as main transcript	n.193-5817G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.00000663

AC:

AN:

150848

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000149

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

250220

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135236

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000886

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000549

AC:

AN:

1456336

Hom.:

Cov.:

AF XY:

0.00000690

AC XY:

AN XY:

724592

show subpopulations

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:

0.00000722

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000663

AC:

AN:

150848

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

73640

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000149

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 13, 2023

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 1309 of the SCN1A protein (p.Leu1309Phe). This variant is present in population databases (rs121918801, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of epileptic encephalopathy (PMID: 20117752). ClinVar contains an entry for this variant (Variation ID: 68625). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SCN1A protein function. This variant disrupts the p.Leu1309 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). 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. -

Severe myoclonic epilepsy in infancy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centogene AG - the Rare Disease Company

Sep 01, 2021

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 03, 2013

The Leu1309Phe missense change has been previously reported in two brothers, one with Dravet syndrome and the other with myoclonic-astatic epilepsy (Dimova et al., 2009). The unaffected mother was negative for the variant; however, the father, who had a history of a single febrile seizure and generalized tonic-clonic seizures, was not tested (Dimova et al., 2009). Leu1309Phe was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is a conservative amino acid substitution of one uncharged, non-polar amino acid for another. However, the variant alters a conserved position in the S4 subunit of the third transmembrane domain and other missense mutations associated with epilepsy have been reported in this region of the protein. In silico analysis is inconsistent with regard to the effect this variant may have on the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. This variant has been observed to be paternally inheritied. The variant is found in INFANT-EPI panel(s). -

Generalized epilepsy with febrile seizures plus, type 1

Other:1

not provided, no classification provided

literature only

UniProtKB/Swiss-Prot

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.47

Cadd

Uncertain

Dann

Uncertain

1.0

Eigen

Uncertain

0.62

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.86

D;D;D;D;.;D;.;.;D;D

M_CAP

Pathogenic

0.70

MetaRNN

Pathogenic

0.88

D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.86

Polyphen

0.33, 1.0

.;.;.;B;D;.;B;D;D;.

Vest4

0.85, 0.93, 0.90, 0.86

MutPred

0.66

.;Gain of ubiquitination at K1313 (P = 0.0985);.;Gain of ubiquitination at K1313 (P = 0.0985);.;.;Gain of ubiquitination at K1313 (P = 0.0985);.;.;.;

MVP

0.97

MPC

1.6

ClinPred

0.95

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.27

gMVP

0.92

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