rs80338957

Positions:

chr17-63957427-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_000334.4(SCN4A):c.2111C>T(p.Thr704Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SCN4A
NM_000334.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:15

Conservation

PhyloP100: 10.0

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 16 ACMG points.

PM1

In a transmembrane_region Helical; Name=S5 of repeat II (size 18) in uniprot entity SCN4A_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000334.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.982

PP5

Variant 17-63957427-G-A is Pathogenic according to our data. Variant chr17-63957427-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 5896.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-63957427-G-A is described in Lovd as [Pathogenic]. Variant chr17-63957427-G-A is described in Lovd as [Likely_pathogenic]. Variant chr17-63957427-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN4A	NM_000334.4 linkuse as main transcript	c.2111C>T	p.Thr704Met	missense_variant	13/24	ENST00000435607.3	NP_000325.4	P35499

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN4A	ENST00000435607.3 linkuse as main transcript	c.2111C>T	p.Thr704Met	missense_variant	13/24	1	NM_000334.4	ENSP00000396320.1		P35499

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

152188

Hom.:

Cov.:

FAILED QC

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461750

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727162

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74342

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:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hyperkalemic periodic paralysis

Pathogenic:6

Pathogenic, no assertion criteria provided	research	Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences	Apr 12, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 704 of the SCN4A protein (p.Thr704Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hyperkalemic periodic paralysis (HYPP), and is the most common cause of HYPP accounting for over 60% of pathogenic alleles (PMID: 15642860, 17395131, 19077043, 22253644, 26256659). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5896). 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 SCN4A protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SCN4A function (PMID: 7809121, 10366610). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Nov 08, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	May 29, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	-	The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.93; 3Cnet: 0.97). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000005896 / PMID: 1659948). The variant has been reported to co-segregate with the disease in at least 7 similarly affected relatives/individuals in at least two unrelated families (PMID: 30172468, 30931713). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2005	- -

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 08, 2021	Most common pathogenic variant associated with hyerkalemic periodic paralysis (hyperKPP) and accounts for approximately 60% of pathogenic alleles (Jurkat-Rott et al., 2003); Functional studies demonstrate that the T704M variant disrupts normal sodium channel function causing a sustained membrane depolarization (Bendahhou et al., 1999); Not observed in large population cohorts (Lek et al., 2016); Identified in patients with periodic paralysis referred for genetic testing at GeneDx as well as in the literature, and often associated with fixed weakness and chronic progressive myopathy; however, phenotypic variability has been described (Lee et al., 2015, Ptacek et al. 1991, Saleem et al., 2013); 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: 23527931, 16870577, 18166706, 12933953, 11309455, 31068157, 7809121, 19077043, 18281721, 26256659, 24082935, 27714768, 28298850, 26834636, 29907477, 30931713, 30369522, 30647473, 31567646, 17395131, 15642860, 15534250, 8985730, 10366610, 22253644, 1659948, 31130284, 32336642, 32849172, 32962503, 32721234, 32528171, 33345742) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 26, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 26, 2022	This is the most common pathogenic variant associated with hyperkalemic periodic paralysis (PMID: 17395131). This variant has not been reported in large, multi-ethnic general populations. (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant interferes with normal sodium channel function (PMID: 10366610, 7809121). -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jul 13, 2022	- -

Hypokalemic periodic paralysis, type 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Aug 16, 2022

PS3, PS4, PM2, PP3 -

Paramyotonia congenita/hyperkalemic periodic paralysis

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2005

- -

Paramyotonia congenita of Von Eulenburg;C0238357:Hyperkalemic periodic paralysis;C2750061:Hypokalemic periodic paralysis, type 2;C2931826:Potassium-aggravated myotonia;C3280112:Congenital myasthenic syndrome 16;C3714580:Hypokalemic periodic paralysis, type 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Sotos syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Oct 01, 2021

PS3, PM2, PP1, PP2, PP3, PP4, PP5 -

SCN4A-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 26, 2023

The SCN4A c.2111C>T variant is predicted to result in the amino acid substitution p.Thr704Met. This variant has been reported in many individuals and families with hyperkalemic periodic paralysis and is one of the most common causative variants in SCN4A for this disorder (Ptácek et al 1991. PubMed ID: 1659948; Jurkat-Rott K et al 2007. PubMed ID: 17395131; Huang S et al 2019. PubMed ID: 30931713; Vereb N et al 2020. PubMed ID: 33263785 ). This variant was also reported in a large Turkish family with hypokalemic periodic paralysis (Gun Bilgic D et al 2020. PubMed ID: 32336642). The c.2111C>T variant has been reported to occur de novo in at least one individual with hyperkalemic periodic paralysis (Han JY et al 2011. PubMed ID: 22253644). Functional studies indicate this variant significantly impairs slow inactivation (Bendahhou S et al 1999. PubMed ID: 10366610). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.96

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.61

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.4

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-5.9

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.033

Polyphen

1.0

Vest4

0.89

MutPred

0.90

Loss of catalytic residue at T704 (P = 0.0224);

MVP

0.96

MPC

0.93

ClinPred

1.0

GERP RS

3.7

Varity_R

0.92

gMVP

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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