17-63943846-C-T

Position:

• chr17-63943846-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000334.4(SCN4A):​c.3917G>A​(p.Gly1306Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN4A NM_000334.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 7.90

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• 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 Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.966
• PP5: Variant 17-63943846-C-T is Pathogenic according to our data. Variant chr17-63943846-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 5920.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-63943846-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN4A	NM_000334.4	c.3917G>A	p.Gly1306Glu	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	c.3917G>A	p.Gly1306Glu	missense_variant	22/24	1	NM_000334.4	ENSP00000396320.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 17, 2024	This variant has not been reported in large, multi-ethnic general populations. (http://gnomad.broadinstitute.org) (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) This variant has been identified in multiple unrelated individuals with clinical features associated with sodium channel myotonia, including individuals where the variant appears to occur de novo. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 7473241, 16392038, 29774303) At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 13, 2021	Observed in multiple unrelated individuals with myotonia in the published literature (Furby et al. 2014; Lion-Francois et al., 2010; Singh et al., 2014); Published functional studies demonstrate a damaging effect as electrophysiological studies showed that G1306E reduced fast inactivation of the channel, as well as delayed channel opening and activation (Lerche et al., 1993; Mitrovic et al., 1995); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Different missense changes at this residue (G1306V) and (G1306A) have been reported in the Human Gene Mutation Database and in the published literature (HGMD; Lerche et al., 1993; Ricker et al., 1994; Lion-Francois et al., 2010; Lampe et al., 2004; McClatchey et al., 1992); This variant is associated with the following publications: (PMID: 20713951, 8308722, 7473241, 16392038, 18723887, 25311598, 25088311, 30611854, 32849172, 32593548, 33084218, 26080010, 16832098, 26834636, 7980103, 23958773, 22016737, 23052413, 20237798, 28199958, 18166706, 29899727, 11723275, 20590641, 26944947, 20076800, 32010054) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jul 13, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2022	SCN4A: PS4, PM2, PM5, PS3:Moderate, PP3, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 01, 2019	- -

Paramyotonia congenita of Von Eulenburg Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Genetics, Royal Melbourne Hospital

Jun 26, 2020

This sequence change is predicted to replace glycine with glutamic acid at codon 1306 of the SCN4A protein (p.(Gly1306Glu)). The glycine residue is very highly conserved (100 vertebrates, UCSC), and is in the cytoplasmic ion transporter region, with a critical role in sodium channel inactivation (PM1, refer to OMIM #603967). There is a moderate physicochemical difference between glycine and glutamic acid. The variant is absent in a large population cohort (PM2, gnomAD v2.1.1 and v3). This variant has been previously reported in over 25 probands with myotonia (PS4, PMID 8308722, 23958773, 20713951, 16832098, 29774303, 25311598, 20076800, 29606556) and segregates with phenotype (PP1, PMID 16832098, 29774303). It has been reported as a de novo change in at least 12 families (PM6_VeryStrong, PMID 23958773, 20713951, 29774303). Functional studies support pathogenicity of the variant (PS3_Supporting, PMID 16392038, 30611854). Muscle biopsy studies demonstrate that p.(Gly1306Glu) affects electrophysiology (PMID 8308722). Multiple lines of computational evidence have conflicting predictions for the missense substitution. A different amino acid change at the same residue has been reported in three families with myotonia fluctuans (PMID 7980103). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant has been classified as PATHOGENIC. The following criteria have been applied: PM6_VeryStrong, PS4, PM1, PM2, PP1, PS3_Supporting. -

SCN4A-related myopathy, autosomal recessive Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

May 06, 2021

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with SCNA4-related disorders. Functional studies of missense variants have demonstrated both a loss and gain of protein function, even for the same phenotype (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 in congential myasthenic syndrome have been reported (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 glycine to glutamic acid (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - Multiple alternative amino acid change at the same position has been observed in gnomAD (highest allele count: 2 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated sodium-channel gate (NCBI). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. At least 30 individuals from 24 families have been reported to harbour this variant, the majority of which arose de novo. This variant has also been classified as pathogenic by diagnostic laboratories in ClinVar (PMID: 32509969). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Hyperkalemic periodic paralysis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 29, 2023

This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 1306 of the SCN4A protein (p.Gly1306Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant SCN4A-related conditions (PMID: 8308722, 16832098, 20713951, 25088311, 25311598, 26944947). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 5920). 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 not expected to disrupt SCN4A protein function with a negative predictive value of 80%. 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, 8308722, 26080010). 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. -

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

May 03, 2022

- -

Potassium-aggravated myotonia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

-

The missense variant p.G1306E in SCN4A (NM_000334.4) has been previously reported in heterozygous state in affected individuals (Singh RR et al; Lion-Francois L).Functional studies suggest a damaging effect (Groome JR et al). A different missense substitution at this codon (p.Gly1306Ala) has been determined to be pathogenic (Torbergsen T et al). The variant has been submitted to ClinVar as Pathogenic. The p.G1306E variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.G1306E missense variant is predicted to be damaging by both SIFT and PolyPhen2. The glycine residue at codon 1306 of SCN4A is conserved in all mammalian species. The nucleotide c.3917 in SCN4A is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

Myotonia permanens Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 11, 2006

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Pathogenic	3.2	M
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-6.0	D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.17	T
Polyphen		0.89	P
Vest4		0.74
MutPred		0.81		Gain of solvent accessibility (P = 0.0171);
MVP		0.85
MPC		0.76
ClinPred		0.99	D
GERP RS		3.4
Varity_R		0.79
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.23		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs80338792; hg19: chr17-62021206; COSMIC: COSV101438458; COSMIC: COSV101438458;