17-63959269-C-T

Position:

chr17-63959269-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5

The NM_000334.4(SCN4A):c.2015G>A(p.Arg672His) variant causes a missense change. The variant allele was found at a frequency of 0.00000343 in 1,458,254 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. R672C) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

SCN4A
NM_000334.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8U:1O:2

Conservation

PhyloP100: 6.17

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 11 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 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 chr17-63959270-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 21151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.99

PP5

Variant 17-63959269-C-T is Pathogenic according to our data. Variant chr17-63959269-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 5912.We mark this variant Likely_pathogenic, oryginal submissions are: {not_provided=2, Pathogenic=6, Uncertain_significance=1}. Variant chr17-63959269-C-T 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.2015G>A	p.Arg672His	missense_variant	12/24	ENST00000435607.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN4A	ENST00000435607.3 linkuse as main transcript	c.2015G>A	p.Arg672His	missense_variant	12/24	1	NM_000334.4	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000121

AC:

AN:

247856

Hom.:

AF XY:

0.00000744

AC XY:

AN XY:

134406

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:

0.0000466

Gnomad NFE exome

AF:

0.0000178

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000343

AC:

AN:

1458254

Hom.:

Cov.:

AF XY:

0.00000414

AC XY:

AN XY:

724910

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:

0.0000188

Gnomad4 NFE exome

AF:

0.00000361

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000496

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000827

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:8Uncertain:1Other:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial hyperkalemic periodic paralysis

Pathogenic:2Uncertain:1Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Uncertain significance, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 25, 2024	- -
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	Dec 31, 2023	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 672 of the SCN4A protein (p.Arg672His). This variant is present in population databases (rs80338788, gnomAD 0.005%). This missense change has been observed in individual(s) with hypokalemic periodic paralysis (PMID: 10944223, 14504341, 15596759, 19225109, 22253645, 23019082, 25213595). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5912). 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: 10944223, 11912116, 18824591). This variant disrupts the p.Arg672 amino acid residue in SCN4A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10944223, 11558801, 11912116, 15482957, 17330043, 18824591, 19225109, 20660662, 25024265, 26252573). 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. -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	SCN4A: PM1, PM2, PM5, PS4:Moderate, PP3, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 14, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 25, 2022	Published functional studies show that R672H alters channel inactivation and decreases current density, thus reducing the number of excitable channels during membrane depolarization (Jurkat-Rott et al., 2000; Sokolov et al., 2010); Not observed at a significant frequency in large population cohorts (gnomAD); Reported previously in at least three families with hypokalemic periodic paralysis type 2 (Jurkat-Rott et al., 2000); 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: 18824591, 20660662, 10944223, 26252573, 20301669, 32619119, 23019082, 19225109, 20301512, 25213595, 25024265, 33144682) -

Hypokalemic periodic paralysis, type 2

Pathogenic:1Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2002	- -

Acetazolamide-responsive myotonia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Sep 07, 2023

Variant summary: SCN4A c.2015G>A (p.Arg672His) results in a non-conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 247856 control chromosomes (gnomAD). c.2015G>A has been reported in the literature in multiple individuals affected with Hypokalaemic periodic paralysis (Jurkat-Rott_2000, Horga_2013). These data indicate that the variant is very likely to be associated with disease. Functional studies reported this variant affects SCN4A protein function (Jurkat-Rott_2000, Struyk_2008, Sokolov_2010). The following publications have been ascertained in the context of this evaluation (PMID: 23516313, 10944223, 20660662, 17591984). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified 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

Mar 30, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.99

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

M_CAP

Pathogenic

0.57

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.0

MutationTaster

Benign

1.0

A;A

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-4.8

REVEL

Pathogenic

0.89

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.045

Vest4

0.96

MutPred

0.99

Loss of MoRF binding (P = 0.0191);

MVP

0.94

MPC

0.99

ClinPred

1.0

GERP RS

4.9

Varity_R

0.91

gMVP

0.95

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