Variant chr17-63941517-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PP3_StrongPP5_Very_Strong

The NM_000334.4(SCN4A):c.4765G>A(p.Val1589Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,884 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 (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

SCN4A
NM_000334.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 7.91

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_000334.4

PP3

MetaRNN computational evidence supports a deleterious effect, 0.972

PP5

Variant 17-63941517-C-T is Pathogenic according to our data. Variant chr17-63941517-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 5905.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-63941517-C-T is described in Lovd as [Pathogenic]. Variant chr17-63941517-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN4A	NM_000334.4 linkuse as main transcript	c.4765G>A	p.Val1589Met	missense_variant	24/24	ENST00000435607.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN4A	ENST00000435607.3 linkuse as main transcript	c.4765G>A	p.Val1589Met	missense_variant	24/24	1	NM_000334.4	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727242

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:

0.00000540

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 10, 2021	Multiple in vitro and in vivo functional studies show that V1589M alters properties of channel inactivation, resulting in faster channel recovery after inactivation. Rapid re-opening of sodium channels most likely underlies the hyperexcitability associated with sodium channel myotonia (Iaizzo et al., 1991; Mitrovi N., et al 1994; Takahashi et al., 2001; Tan et al., 2018); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 16624558, 32670189, 25755818, 27415035, 9771789, 1668369, 28877545, 7965854, 21664816, 29050397, 28378410, 18166706, 8242056, 11744749) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 19, 2021	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant appears to occur de novo in multiple individuals with clinical features associated with this gene. This variant segregates with disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant leads to impaired SCN4A channel activity (PMID: 7965854). -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 30, 2022	- -

Paramyotonia congenita of Von Eulenburg

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Sep 10, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 1998	- -

Hypokalemic periodic paralysis, type 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

DASA

Mar 05, 2022

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 11744749; 7965854; 8242056) - PS3_moderate.The c.4765G>A;p.(Val1589Met) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 5905; PMID: 25755818; PMID: 9771789; PMID: 23810313; PMID:23771340; PMID: 18166706; PMID: 16624558) - PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (Ion_trans; PKD_channel) - PM1. This variant is not present in population databases (rs121908548- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The variant co-segregated with disease in multiple affected family members (PMID: 25755818; 16624558; 9771789) - PP1_strong. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. -

Hyperkalemic periodic paralysis

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 10, 2023

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SCN4A function (PMID: 11744749). 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. ClinVar contains an entry for this variant (Variation ID: 5905). This missense change has been observed in individuals with paramyotonia congenita (PMID: 8242056, 9771789, 18166706, 23771340, 23810313, 25755818). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1589 of the SCN4A protein (p.Val1589Met). -

Potassium-aggravated myotonia

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 1998

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.84

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.70

M_CAP

Pathogenic

0.47

MetaRNN

Pathogenic

0.97

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.3

MutationTaster

Benign

1.0

A;A

PrimateAI

Pathogenic

0.94

PROVEAN

Uncertain

-2.5

REVEL

Pathogenic

0.90

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.049

Polyphen

1.0

Vest4

0.91

MutPred

0.89

Loss of catalytic residue at V1589 (P = 0.0261);

MVP

0.95

MPC

0.91

ClinPred

0.99

GERP RS

3.9

Varity_R

0.88

gMVP

0.78

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

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