rs199473250

chr3-38556536-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP2

The NM_001099404.2(SCN5A):c.4342A>C(p.Ile1448Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000378 in 1,612,560 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1448T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000039 (0 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:8 O:1
• Conservation: PhyloP100: 1.30

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_001099404.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-38556535-A-G is described in Lovd as [Pathogenic].
• PP2: Missense variant where missense usually causes diseases, SCN5A

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2	c.4342A>C	p.Ile1448Leu	missense_variant	25/28	ENST00000413689.6
SCN5A	NM_000335.5	c.4339A>C	p.Ile1447Leu	missense_variant	25/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.4342A>C	p.Ile1448Leu	missense_variant	25/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.4339A>C	p.Ile1447Leu	missense_variant	25/28	1	NM_000335.5	A1

Frequencies

GnomAD3 genomes AF: 0.0000264 AC: 4 AN: 151454 Hom.: 0 Cov.: 32

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000362 AC: 9 AN: 248530 Hom.: 0 AF XY: 0.0000223 AC XY: 3 AN XY: 134748

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.0000621

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000390 AC: 57 AN: 1461106 Hom.: 0 Cov.: 36 AF XY: 0.0000413 AC XY: 30 AN XY: 726728

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000672

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.0000387

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000264 AC: 4 AN: 151454 Hom.: 0 Cov.: 32 AF XY: 0.0000271 AC XY: 2 AN XY: 73918

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000278 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000248 AC: 3

EpiCase AF: 0.000164

EpiControl AF: 0.0000594

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 17, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 13, 2023	This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1448 of the SCN5A protein (p.Ile1448Leu). This variant is present in population databases (rs199473250, gnomAD 0.005%). This missense change has been observed in individual(s) with SCN5A-related conditions (PMID: 20129283, 25351510). ClinVar contains an entry for this variant (Variation ID: 67882). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Cardiac arrhythmia Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 13, 2023	This missense variant replaces isoleucine with leucine at codon 1448 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Brugada syndrome, hypertrophic cardiomyopathy, long QT syndrome, and dilated cardiomyopathy (PMID: 20129283, 25904541, 25351510, 27566755, 34935411). This variant has been identified in 9/248530 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 28, 2023	This missense variant replaces isoleucine with leucine at codon 1448 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Brugada syndrome, hypertrophic cardiomyopathy, long QT syndrome, and dilated cardiomyopathy (PMID: 20129283, 25904541, 25351510, 27566755, 34935411). This variant has been identified in 9/248530 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 13, 2014

Variant classified as Uncertain Significance - Favor Benign. The p.Ile1448Leu va riant in SCN5A has been reported in 1 individual with Brugada syndrome (Kappling er 2010) and was absent from large population studies. Isoleucine (Ile) at posit ion 1448 is not conserved in mammals or evolutionarily distant species and oposs um, Tasmanian devil, wallaby, and multiple birds and fish species carry a leucin e (Leu) at this position, suggesting that this change may be tolerated. Addition al computational prediction tools suggest that this variant may not impact the p rotein, though this information is not predictive enough to rule out pathogenici ty. In summary, while the clinical significance of the p.Ile1448Leu variant is u ncertain, the presence of the variant amino acid in multiple other species, incl uding mammals, suggests that it is more likely to be benign. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 06, 2022

- -

Long QT syndrome 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Jul 04, 2022

ACMG classification criteria: PS4 supporting, PM2 moderated -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 09, 2022

The c.4342A>C (p.I1448L) alteration is located in exon 25 (coding exon 24) of the SCN5A gene. This alteration results from a A to C substitution at nucleotide position 4342, causing the isoleucine (I) at amino acid position 1448 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Brugada 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 Brugada syndrome in the following publications (PMID:20129283). 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	Benign	0.051
CardioboostArm	Benign	0.000096
CardioboostCm	Benign	0.062
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.18
Cadd	Benign	16
Dann	Benign	0.55
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.72	D
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.57	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.18	D
MutationTaster	Benign	0.82	D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	0.65	N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.53
Sift	Benign	1.0	T;T;T;T;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T;T
Polyphen		0.0010	B;B;.;B;.;B;B;.;.
Vest4		0.75
MutPred		0.87		.;.;Loss of sheet (P = 0.0181);.;.;Loss of sheet (P = 0.0181);.;.;.;
MVP		0.95
MPC		0.51
ClinPred		0.050	T
GERP RS		1.8
Varity_R		0.16
gMVP		0.94

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: rs199473250; hg19: chr3-38598027;