rs80338792

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000334.4(SCN4A):c.3917G>T(p.Gly1306Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,449,642 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1306A) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SCN4A
NM_000334.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 7.90

Variant links:

Genes affected

SCN4A (HGNC:10591): (sodium voltage-gated channel alpha subunit 4) Voltage-gated sodium channels are transmembrane glycoprotein complexes composed of a large alpha subunit with 24 transmembrane domains and one or more regulatory beta subunits. They are responsible for the generation and propagation of action potentials in neurons and muscle. This gene encodes one member of the sodium channel alpha subunit gene family. It is expressed in skeletal muscle, and mutations in this gene have been linked to several myotonia and periodic paralysis disorders. [provided by RefSeq, Jul 2008]

SCN4A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000334.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-63943846-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 5908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.967

PP5

Variant 17-63943846-C-A is Pathogenic according to our data. Variant chr17-63943846-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 5903.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-63943846-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN4A	NM_000334.4 linkuse as main transcript	c.3917G>T	p.Gly1306Val	missense_variant	22/24	ENST00000435607.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN4A	ENST00000435607.3 linkuse as main transcript	c.3917G>T	p.Gly1306Val	missense_variant	22/24	1	NM_000334.4	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249512

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135334

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:

0.00000885

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1449642

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

721982

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:

0.00000182

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Paramyotonia congenita of Von Eulenburg

Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Oct 25, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.92; 3Cnet: 0.91). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000005903). The variant has been reported to co-segregate with the disease in at least 3 similarly affected relatives/individuals in the same family or similarly affected unrelated families (PMID: 27415035). Different missense changes at the same codon (p.Gly1306Ala, p.Gly1306Glu) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000005908, VCV000005920). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 03, 2023	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant associates with paramyotonia congenita in multiple families, and is reported in multiple other unrelated individuals with non-dystrophic myotonia. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic. Assessment of experimental evidence suggests this variant results in abnormal protein function. Multiple studies indicate that this variant disrupts normal ion channel properties, resulting in aberrant channel regulation of current and signaling (PMID: 7473241, 16392038). -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	SCN4A: PM2, PM5, PP1:Moderate, PS4:Moderate, PP3, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 13, 2021	Reported previously as a heterozygous variant in two unrelated families with paramyotonia congenita (McClatchey et al., 1992); Functional studies suggest that G1306V results in slower inactivation of the SCN4A sodium channel (Lerche et al., 1993); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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: 25525159, 8308722, 1310898, 27415035, 26944947, 18337100, 18337730, 28150151, 26885337, 26080010, 22094069, 20445432, 17823953, 16832098, 8044656, 16392038, 7473241, 32849172, 32660787) -

Familial hyperkalemic periodic paralysis

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 11, 2023	This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1306 of the SCN4A protein (p.Gly1306Val). This variant is present in population databases (rs80338792, gnomAD 0.0009%). This missense change has been observed in individuals with paramyotonia congenita (PMID: 1310898, 8044656, 8308722, 17823953, 18337100, 18337730, 20445432, 22094069, 27415035). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5903). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SCN4A protein function. Experimental studies have shown that this missense change affects SCN4A function (PMID: 7473241, 16392038). This variant disrupts the p.Gly1306 amino acid residue in SCN4A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7980103, 16832098, 20713951, 25088311, 25311598, 26080010, 26885337, 26944947). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2016	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP2,PP3. -

SCN4A-related non-dystrophic myotonia

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences

Apr 06, 2022

- -

Potassium-aggravated myotonia

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 2009

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.65

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.84

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.88

MetaRNN

Pathogenic

0.97

MetaSVM

Pathogenic

1.2

MutationAssessor

Pathogenic

4.5

MutationTaster

Benign

0.99

D;D

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-6.9

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

0.80

Vest4

0.75

MutPred

0.81

Loss of disorder (P = 0.0258);

MVP

0.88

MPC

0.52

ClinPred

0.99

GERP RS

3.4

Varity_R

0.81

gMVP

0.64

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