rs121908547

Positions:

chr17-63943825-G-A

Variant summary

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

The ENST00000435607.3(SCN4A):c.3938C>T(p.Thr1313Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,054 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1313A) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SCN4A
ENST00000435607.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 9.99

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 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in ENST00000435607.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-63943826-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 2736637.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.975

PP5

Variant 17-63943825-G-A is Pathogenic according to our data. Variant chr17-63943825-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 5904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-63943825-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.3938C>T	p.Thr1313Met	missense_variant	22/24	ENST00000435607.3	NP_000325.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN4A	ENST00000435607.3 linkuse as main transcript	c.3938C>T	p.Thr1313Met	missense_variant	22/24	1	NM_000334.4	ENSP00000396320	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

249794

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135450

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:

0.00000884

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460054

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726466

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

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	Jan 01, 2011	- -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Jan 14, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	May 18, 2022	- -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 19, 2022	The frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant has been identified in individuals with paramyotonia congenita and segregates with disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. Studies showed impaired sodium channel inactivation (PMID: 7809121, 8740371, 8910215, 9130156, 14617673, 30611854). -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 10, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 13, 2022	Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect as T1313M alters channel inactivation and voltage dependence compared to wild-type controls (Yang et al., 1994); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported as a common pathogenic variant associated with paramyotonia congenita; This variant is associated with the following publications: (PMID: 8583225, 27199537, 8910215, 8740371, 29790872, 11054753, 32083589, 1310898, 27415035, 12872329, 10206477, 9130156, 7533571, 28877545, 30611854, 31567646, 32849172, 32670189, 33430134, 21220685, 30647473, 15318338, 7809121, 32660787) -

SCN4A-related myopathy, autosomal recessive

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Feb 02, 2022

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function (LoF) and gain of function (GoF) are known mechanisms of disease in this gene and are associated with SCN4A-related disease. GoF is a well characterised disease mechanism for autosomal dominant SCN4A-related diseases, while LoF is a mechanism associated with autosomal recessive SCN4A-related diseases (PMID: 26700687, OMIM). (I) 0108 - This gene is associated with both recessive and dominant disease. Variants in this gene are usually inherited in a dominant manner, however rare reports of recessive inheritance have been reported (PMID: 24549961, OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity. Some individuals carrying pathogenic variants do not present with a typical clinical phenotype, however they do have detectable signs of myotonia on EMG (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from threonine to methionine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (1 heterozygote, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the putative hydrophobic latch of the annotated sodium channel gate domain (NCBI). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This is one of the most frequently reported variants in individuals with paramyotonia congenita (ClinVar, PMID: 30647473, 32849172, 33430134). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

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

- -

Familial hyperkalemic periodic paralysis

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 19, 2023

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1313 of the SCN4A protein (p.Thr1313Met). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with autosomal dominant paramyotonia congenita (PMID: 1310898, 8044656, 14518676, 15790667, 18166706, 18337730, 19770477, 20445432, 21220685, 23771340, 23810313, 26834636, 27199537). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5904). 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 95%. Experimental studies have shown that this missense change affects SCN4A function (PMID: 7809121, 8910215). For these reasons, this variant has been classified as Pathogenic. -

SCN4A-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 03, 2023

The SCN4A c.3938C>T variant is predicted to result in the amino acid substitution p.Thr1313Met. This variant has been reported in many individuals to be causative for paramyotonia congenita (McClatchey et al. 1992. PubMed ID: 1310898; Matthews et al. 2011. PubMed ID: 21220685). Functional studies suggest that the p.Thr1313Met substitution causes a disturbance in sodium channel inactivation (Yang et al. 1994. PubMed ID: 7809121). A different substitution at the same amino acid (p.Thr1313Ala) has also been observed in a patient with paramyotonia congenita, and may induce defects in sodium channel inactivation (Bouhours et al. 2003. PubMed ID: 14617673). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-62021185-G-A). This variant is interpreted as pathogenic. -

Paramyotonia congenita of Von Eulenburg;C0238357:Familial 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

- -

Congenital myasthenic syndrome 16

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 30, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.91

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.91

M_CAP

Pathogenic

0.64

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.8

MutationTaster

Benign

1.0

A;A

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-5.8

REVEL

Pathogenic

0.96

Sift

Uncertain

0.0070

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.82

MutPred

0.87

Gain of loop (P = 0.0502);

MVP

0.95

MPC

0.92

ClinPred

1.0

GERP RS

3.4

Varity_R

0.57

gMVP

0.81

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