3-38613790-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5

The NM_000335.5(SCN5A):c.656G>A(p.Arg219His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,610,664 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/22 in silico tools predict a damaging 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. R219C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SCN5A
NM_000335.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7U:1

Conservation

PhyloP100: 7.91

Publications

38 publications found

Variant links:

Genes affected

SCN5A (HGNC:10593): (sodium voltage-gated channel alpha subunit 5) The protein encoded by this gene is an integral membrane protein and tetrodotoxin-resistant voltage-gated sodium channel subunit. This protein is found primarily in cardiac muscle and is responsible for the initial upstroke of the action potential in an electrocardiogram. Defects in this gene have been associated with long QT syndrome type 3 (LQT3), atrial fibrillation, cardiomyopathy, and Brugada syndrome 1, all autosomal dominant cardiac diseases. Alternative splicing results in several transcript variants encoding different isoforms. [provided by RefSeq, May 2022]

SCN5A Gene-Disease associations (from GenCC):

Brugada syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Brugada syndrome 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Laboratory for Molecular Medicine, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
dilated cardiomyopathy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
dilated cardiomyopathy 1E
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
familial long QT syndrome
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
long QT syndrome 3
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
sick sinus syndrome 1
Inheritance: AD, AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
progressive familial heart block, type 1A
Inheritance: SD, AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp
atrial standstill
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial atrial fibrillation
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial sick sinus syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
paroxysmal familial ventricular fibrillation
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
progressive familial heart block
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
arrhythmogenic right ventricular cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
catecholaminergic polymorphic ventricular tachycardia
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
short QT syndrome
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

SCN5A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 12 uncertain in NM_000335.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-38613791-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 432157.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.992

PP5

Variant 3-38613790-C-T is Pathogenic according to our data. Variant chr3-38613790-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 242206.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_000335.5 link	c.656G>A	p.Arg219His	missense_variant	Exon 6 of 28	ENST00000423572.7	NP_000326.2	Q14524-2Q86V90
SCN5A	NM_001099404.2 link	c.703+185G>A		intron_variant	Intron 6 of 27	ENST00000413689.6	NP_001092874.1	Q14524H9KVD2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000423572.7 link	c.656G>A	p.Arg219His	missense_variant	Exon 6 of 28	1	NM_000335.5	ENSP00000398266.2		Q14524-2
SCN5A	ENST00000413689.6 link	c.703+185G>A		intron_variant	Intron 6 of 27	5	NM_001099404.2	ENSP00000410257.1		H9KVD2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152116

Hom.:

Cov.:

show subpopulations

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

244110

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1458548

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725156

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33424

American (AMR)

AF:

0.00

AC:

AN:

44348

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26050

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39634

South Asian (SAS)

AF:

0.00

AC:

AN:

85350

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53214

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

9.01e-7

AC:

AN:

1110490

Other (OTH)

AF:

0.00

AC:

AN:

60276

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152116

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74310

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41396

American (AMR)

AF:

0.00

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Dec 11, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 219 of the SCN5A protein (p.Arg219His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of SCN5A-related conditions (PMID: 22675453, 24762805, 26304136). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 242206). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects SCN5A function (PMID: 22675453, 24762805, 30218094). This variant disrupts the p.Arg219 amino acid residue in SCN5A. Other variant(s) that disrupt this residue have been observed in individuals with SCN5A-related conditions (PMID: 30193851), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Sep 27, 2024

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported in association with DCM and arrhythmia (PMID: 22675453, 26304136); Published functional studies demonstrate a damaging effect as this variant causes a delayed recovery from inactivation (PMID: 24762805); 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; This variant is associated with the following publications: (PMID: 23818691, 24815523, 28018021, 25624448, 26801742, 26304136, 25741286, 28469493, 30218094, 30662450, 24762805, 34949099, 35650162, 38820625, 38232626, 22675453, 33640350) -

Cardiovascular phenotype

Pathogenic:2

Oct 10, 2024

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R219H pathogenic mutation (also known as c.656G>A), located in coding exon 5 of the SCN5A gene, results from a G to A substitution at nucleotide position 656. The arginine at codon 219 is replaced by histidine, an amino acid with highly similar properties, and is located in the voltage sensing S4 region. This alteration was detected in a proband with cardiac conduction disease and mild dilated cardiomyopathy (DCM), and in two relatives with mild to borderline DCM (Gosselin-Badaroudine P et al. PLoS ONE. 2012;7:e38331). This alteration was also detected in two probands with sick sinus syndrome (SSS) and atrial arrhythmia or paralysis, and segregated with disease in two similarly affected relatives in one family (Robles C et al. Rev Esp Cardiol (Engl Ed). 2015;68:904-6; Abe K et al. Circ Arrhythm Electrophysiol. 2014;7:511-7). One in vitro functional study reported this alteration to result in a channel which selectively leaked protons, although channel kinetics were not impacted, while a second study reported this alteration to result in altered channel currents (Abe K et al. Circ Arrhythm Electrophysiol. 2014;7:511-7). Internal structural analysis has determined this alteration occurs at a position directly impacting the ion transport function. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Feb 23, 2024

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PS3_mod;PS4_mod;PM1_supp;PM2;PP1;PP2;PP3 -

Cardiomyopathy

Pathogenic:1

Apr 04, 2023

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Primary familial dilated cardiomyopathy

Pathogenic:1

Sep 30, 2024

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: SCN5A c.656G>A (p.Arg219His) results in a non-conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.9e-06 in 1610664 control chromosomes (gnomAD). c.656G>A has been reported in the literature in multiple individuals affected with Dilated Cardiomyopathy, sick sinus syndrome, or paralysis of the atrium. These data indicate that the variant is very likely to be associated with disease. Publications report experimental evidence evaluating an impact on protein function, finding that the variant alters channel function (e.g. Abe_2014). The following publications have been ascertained in the context of this evaluation (PMID: 22675453, 24762805, 26304136). ClinVar contains an entry for this variant (Variation ID: 242206). Based on the evidence outlined above, the variant was classified as pathogenic. -

Cardiac arrhythmia

Pathogenic:1

Nov 25, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces arginine with histidine at codon 219 of the SCN5A protein. This variant is found within the highly conserved S4 segment of transmembrane domain DI (a.a. 127-415). Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with Brugada syndrome and long QT syndrome (PMID: 32893267). Multiple functional studies have shown that this variant impairs sodium channel function (PMID: 22675453, 24762805, 30218094, 38820625). The variant has been reported in a proband with a mixed phenotype of arrhythmia and dilated cardiomyopathy (PMID: 22675453) and in two probands affected with sick sinus syndrome (PMID: 24762805, 26304136). It has been shown that this variant segregates with disease in two of these families (PMID: 22675453, 26304136). The variant has also been observed in an individual affected with Brugda syndrome and in other individuals affected with arrhythmia or arrhythmogenic right ventricular cardiomyopathy (communication with an external laboratory; ClinVar SCV000583001.6). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

not specified

Uncertain:1

Jan 14, 2021

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg219His variant in SCN5A has been reported in 2 individuals with sick sinus syndrome (SSS) and 1 individual with DCM and conduction disorder. The variant segregated with disease in 2 relatives with DCM and premature ventricular contractions and 2 members of a different family with SSS (Abe 2014 PMID: 24762805, Gosselin-Badaroudine 2012 PMID: 22675453, Robles 2015 PMID: 26304136). This variant was also observed in 3 unaffected relatives (Abe 2014 PMID: 24762805, Robles 2015 PMID: 26304136). It was absent from large population studies, but has been reported in ClinVar (Variation ID: 242206). In vitro functional studies provide some evidence that this variant impacts protein function (Abe 2014 PMID: 24762805, Gosselin-Badaroudine 2012 PMID: 22675453); however, these types of assays may not accurately represent biological function. Additionally, computational prediction tools and conservation analysis suggest that the p.Arg219His variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PP1, PP3, PS3_Supporting, PS4_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

CardioboostArm

Pathogenic

0.99

CardioboostCm

Uncertain

0.88

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.99

.;D;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.91

D;D;D

M_CAP

Pathogenic

0.96

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.4

H;H;.

PhyloP100

7.9

PROVEAN

Pathogenic

-4.9

D;D;D

REVEL

Pathogenic

0.99

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.99

MutPred

0.89

Loss of MoRF binding (P = 0.0272);Loss of MoRF binding (P = 0.0272);Loss of MoRF binding (P = 0.0272);

MVP

0.99

ClinPred

1.0

GERP RS

4.3

Varity_R

0.94

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over