3-38587404-C-T

Variant names:

• chr3-38587404-C-T
• rs769349991
• NM_001099404.2:c.2432G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM5 PP3_Strong PP5

The NM_001099404.2(SCN5A):​c.2432G>A​(p.Arg811His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,458,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 16/24 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. R811C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3
• Conservation: PhyloP100: 7.91
• Publications: 17 publications found

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 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, 9 uncertain in NM_001099404.2
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-38587405-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 201474.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98
• PP5: Variant 3-38587404-C-T is Pathogenic according to our data. Variant chr3-38587404-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 519424.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.2432G>A	p.Arg811His	missense_variant	Exon 15 of 28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.2432G>A	p.Arg811His	missense_variant	Exon 15 of 28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.2432G>A	p.Arg811His	missense_variant	Exon 15 of 28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.2432G>A	p.Arg811His	missense_variant	Exon 15 of 28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000122 AC: 3 AN: 246616 AF XY: 0.0000225

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

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: 0.00000548 AC: 8 AN: 1458840 Hom.: 0 Cov.: 31 AF XY: 0.00000827 AC XY: 6 AN XY: 725260

African (AFR) AF: 0.00 AC: 0 AN: 33434

American (AMR) AF: 0.0000224 AC: 1 AN: 44588

Ashkenazi Jewish (ASJ) AF: 0.0000385 AC: 1 AN: 25966

East Asian (EAS) AF: 0.00 AC: 0 AN: 39656

South Asian (SAS) AF: 0.0000467 AC: 4 AN: 85716

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53308

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110206

Other (OTH) AF: 0.00 AC: 0 AN: 60248

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000409 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000825 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Nov 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

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 811 of the SCN5A protein (p.Arg811His). This variant is present in population databases (rs769349991, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of SCN5A-related conditions (PMID: 23424222, 35063694). ClinVar contains an entry for this variant (Variation ID: 519424). 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: 23424222). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Dec 02, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect through significant loss of function in peak sodium current density and alteration of inactivation and recovery from inactivation (PMID: 23424222); 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: 28573431, 27810048, 30662450, 34697415, 33131149, 30203441, 23424222, 35063694, 30079003) -

SUDDEN INFANT DEATH SYNDROME;C1832680:Dilated cardiomyopathy 1E;C1837845:Sick sinus syndrome 1;C1859062:Long QT syndrome 3;C1879286:Progressive familial heart block, type 1A;C2751898:Ventricular fibrillation, paroxysmal familial, type 1;C3151464:Atrial fibrillation, familial, 10;C4551804:Brugada syndrome 1 Uncertain:1

Aug 20, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Uncertain:1

Aug 22, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R811H variant (also known as c.2432G>A), located in coding exon 14 of the SCN5A gene, results from a G to A substitution at nucleotide position 2432. The arginine at codon 811 is replaced by histidine, an amino acid with highly similar properties. This variant was detected in trans with a second SCN5A variant (p.R620H) in a proband with Brugada syndrome (BrS). The proband's father who had only the p.R811H variant was asymptomatic but had a type I BrS pattern on ECG. The proband's brother, also with only the p.R811H variant, had a normal ECG. The proband's mother and daughters had only the p.R620H variant and were asymptomatic with normal ECGs (Calloe K et al. Circ Arrhythm Electrophysiol, 2013 Feb;6:177-84). Induced pluripotent stem cells derived from the patient's skin fibroblast showed some differences in channel activity (Liang P et al. J. Am. Coll. Cardiol., 2016 Nov;68:2086-2096). In in vitro studies by one group, the p.R811H alteration resulted in reduced peak current density and negative shift of V1/2 of inactivation, while the p.R620H alteration appeared not to affect channel activity nor modify p.R811H when the variants were co-expressed (Calloe K et al. Circ Arrhythm Electrophysiol, 2013 Feb;6:177-84). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
CardioboostArm	Pathogenic	1.0
CardioboostCm	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	.;.;.;.;.;D;.;.;.
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.92	.;D;D;D;D;D;D;.;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	4.4	.;H;.;.;.;H;.;.;.
PhyloP100		7.9
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-4.9	D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.024	D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;.;D;.;P;P;.;.
Vest4		0.98
MutPred		0.88		Loss of MoRF binding (P = 0.0202);Loss of MoRF binding (P = 0.0202);Loss of MoRF binding (P = 0.0202);Loss of MoRF binding (P = 0.0202);Loss of MoRF binding (P = 0.0202);Loss of MoRF binding (P = 0.0202);Loss of MoRF binding (P = 0.0202);Loss of MoRF binding (P = 0.0202);Loss of MoRF binding (P = 0.0202);
MVP		1.0
MPC		0.97
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.93
gMVP		0.98
Mutation Taster		=0/100	disease causing

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

Other links and lift over

dbSNP: rs769349991; hg19: chr3-38628895; COSMIC: COSV61128055;