3-38566576-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_001099404.2(SCN5A):c.3673G>A(p.Glu1225Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,388 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/23 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. E1225Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1 O:1
• Conservation: PhyloP100: 7.91

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_001099404.2
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SCN5A
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 3-38566576-C-T is Pathogenic according to our data. Variant chr3-38566576-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 67810.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, not_provided=1, Uncertain_significance=1, Pathogenic=1}. Variant chr3-38566576-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2	c.3673G>A	p.Glu1225Lys	missense_variant	21/28	ENST00000413689.6
SCN5A	NM_000335.5	c.3670G>A	p.Glu1224Lys	missense_variant	21/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.3673G>A	p.Glu1225Lys	missense_variant	21/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.3670G>A	p.Glu1224Lys	missense_variant	21/28	1	NM_000335.5	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249528 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135354

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: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461388 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726984

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: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 05, 2024	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1225 of the SCN5A protein (p.Glu1225Lys). This variant is present in population databases (rs199473204, gnomAD no frequency). This missense change has been observed in individuals with Brugada syndrome (PMID: 22840528, 23321620, 24136861, 28341781, 28781330, 29574140, 30193851, 31737537). ClinVar contains an entry for this variant (Variation ID: 67810). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 32533946) did not meet the statistical confidence thresholds required to predict the impact of this variant on SCN5A function. Experimental studies have shown that this missense change affects SCN5A function (PMID: 34219138). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 22, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 03, 2023	Reported previously in multiple individuals with definitive or suspected Brugada syndrome (Smits et al., 2002; Schulze-Bahr et al., 2003; Kapplinger et al., 2010; Crotti et al., 2012) or LQTS (Tester et al., 2005); Published functional studies suggest the variant results in loss of protein function (Ishikawa et al., 2021); 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: 24136861, 15840476, 20129283, 34461752, 19606473, 23424222, 22840528, 22581653, 28341781, 32533946, 31737537, 34219138, 33131149, 30662450, 33221895, 29574140, 30193851, 12106943, 14961552, 30203441, 23321620, 28781330, 33164571, 36516610, 37061847) -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 15, 2023

The p.E1225K variant (also known as c.3673G>A), located in coding exon 20 of the SCN5A gene, results from a G to A substitution at nucleotide position 3673. The glutamic acid at codon 1225 is replaced by lysine, an amino acid with similar properties. This variant has been reported in individuals with Brugada syndrome (Smits JP et al. J Am Coll Cardiol, 2002 Jul;40:350-6; Crotti L et al. J Am Coll Cardiol, 2012 Oct;60:1410-8; Sommariva E et al. Eur J Hum Genet, 2013 Sep;21:911-7; Van Malderen SCH et al. Circ J, 2017 Dec;82:53-61; Sonoda K et al. Heart Rhythm, 2018 Aug;15:1179-1188). In vitro studies showed this alteration reduces peak current density (Glazer AM et al. Am J Hum Genet, 2020 Jul;107:111-123; Ishikawa T et al. Eur Heart J, 2021 Jul;42:2854-2863; Salvarani N et al. Int J Mol Sci, 2023 May;24:[ePub ahead of print]). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Cardiac arrhythmia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Nov 16, 2022

This missense variant replaces glutamic acid with lysine at codon 1225 in the transmembrane domain DIII of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). An electrophysiological functional study has shown that this variant results in partial loss of sodium channel function (PMID: 34219138). This variant has been reported in over ten individuals affected with Brugada syndrome (PMID: 22840528, 23321620, 24136861, 28341781, 28781330, 29574140, 30193851, 31737537, 34219138). This variant has been identified in 1/249528 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Brugada syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Jan 01, 2019

- -

Congenital long QT syndrome Other:1

not provided, no classification provided

literature only

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

-

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:15840476). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
CardioboostArm	Pathogenic	1.0
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.9	D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D;D
Polyphen		0.97	D;D;.;D;.;D;D;.;.
Vest4		0.99
MutPred		0.94		Gain of methylation at E1225 (P = 0.0338);.;Gain of methylation at E1225 (P = 0.0338);Gain of methylation at E1225 (P = 0.0338);.;Gain of methylation at E1225 (P = 0.0338);.;.;.;
MVP		0.97
MPC		1.3
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.97
gMVP		0.96

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

Other links and lift over

dbSNP: rs199473204; hg19: chr3-38608067; COSMIC: COSV61128715;