rs199473133

Variant names:

• chr3-38603747-G-A
• rs199473133
• NM_001099404.2:c.1855C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-38603747-G-A
• chr3-38603747-G-C
• chr3-38603747-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_000335.5(SCN5A):​c.1855C>T​(p.Leu619Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000502 in 1,534,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000049 (0 hom.)
• Consequence: SCN5A NM_000335.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:8 O:1
• Conservation: PhyloP100: 6.60

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the SCN5A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 99 curated pathogenic missense variants (we use a threshold of 10). The gene has 60 curated benign missense variants. Gene score misZ: 2.7504 (below the threshold of 3.09). Trascript score misZ: 4.8279 (above the threshold of 3.09). GenCC associations: The gene is linked to progressive familial heart block, type 1A, Brugada syndrome, familial sick sinus syndrome, short QT syndrome, paroxysmal familial ventricular fibrillation, progressive familial heart block, long QT syndrome 3, familial atrial fibrillation, catecholaminergic polymorphic ventricular tachycardia, dilated cardiomyopathy, dilated cardiomyopathy 1E, arrhythmogenic right ventricular cardiomyopathy, Brugada syndrome 1, atrial standstill, familial isolated dilated cardiomyopathy, familial long QT syndrome, sick sinus syndrome 1.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.83

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.1855C>T	p.Leu619Phe	missense_variant	Exon 12 of 28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.1855C>T	p.Leu619Phe	missense_variant	Exon 12 of 28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.1855C>T	p.Leu619Phe	missense_variant	Exon 12 of 28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.1855C>T	p.Leu619Phe	missense_variant	Exon 12 of 28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000313 AC: 6 AN: 191946 Hom.: 0 AF XY: 0.0000197 AC XY: 2 AN XY: 101346

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: 0.0000660

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000492 AC: 68 AN: 1382608 Hom.: 0 Cov.: 30 AF XY: 0.0000502 AC XY: 34 AN XY: 677598

Gnomad4 AFR exome AF: 0.0000319

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: 0.0000616

Gnomad4 OTH exome AF: 0.0000176

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152170 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74348

Gnomad4 AFR AF: 0.0000241

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: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000101 Hom.: 0

Bravo AF: 0.0000453

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000238 AC: 2

ExAC AF: 0.0000333 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Oct 26, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in the literature in patients with LQTS or Brugada syndrome; however, segregation data are uninformative, and some individuals harbor additional variants in other genes (PMID: 12673799, 14998624, 20129283, 30193851); Published functional studies demonstrate a damaging effect; variant expressed in HEK cells results in increased sustained sodium channel current compared to wild-type, causing prolonged depolarization and a speeding of recovery from inactivation (PMID: 12673799); however, this in vitro assay may not accurately represent biological function; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Variant occurs at a position within the cytoplasmic linker connecting domains I and II of the sodium channel that is conserved in mammals (PMID: 12673799); This variant is associated with the following publications: (PMID: 19027780, 29728395, 23414114, 22378279, 25637381, 14998624, 17504259, 12673799, 31589614, 26582918, 30193851, 30203441, 20129283) -

Nov 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 619 of the SCN5A protein (p.Leu619Phe). This variant is present in population databases (rs199473133, gnomAD 0.008%). This missense change has been observed in individuals with SCN5A-related conditions (PMID: 12673799, 30193851). ClinVar contains an entry for this variant (Variation ID: 67693). 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: 12673799). 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

Apr 16, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces leucine with phenylalanine at codon 619 of the SCN5A protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). An experimental functional study has shown that this variant may impact the cardiac sodium channel function of the SCN5A protein (PMID: 12673799). This variant has been reported in two infants affected with long QT syndrome (PMID: 12673799, 14998624) as well as in two unaffected family members of one infant (PMID: 12673799). It has also been reported in individuals affected with Brugada syndrome (PMID: 20129283, 30193851). One of these individuals also carried a pathogenic variant in the same gene (PMID: 20129283). Additionally, this variant has been reported in two individuals in a healthy control population (PMID: 23414114). This variant has been identified in 9/223308 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. -

Mar 20, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces leucine with phenylalanine at codon 619 of the SCN5A protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). An experimental functional study has shown that this variant may impact the cardiac sodium channel function of the SCN5A protein (PMID: 12673799). This variant has been reported in two infants affected with long QT syndrome (PMID: 12673799, 14998624) as well as in two unaffected family members of one infant (PMID: 12673799). It has also been reported in individuals affected with Brugada syndrome (PMID: 20129283, 30193851). One of these individuals also carried a pathogenic variant in the same gene (PMID: 20129283). Additionally, this variant has been reported in two individuals in a healthy control population (PMID: 23414114). This variant has been identified in 9/223308 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. -

SCN5A-related disorder Uncertain:1

Nov 21, 2022

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SCN5A c.1855C>T variant is predicted to result in the amino acid substitution p.Leu619Phe. This variant has been reported in multiple individuals with Long QT or Brugada syndrome (Wehrens et al. 2003. PubMed ID: 12673799; Lupoglazoff et al. 2004. PubMed ID: 14998624; Kapplinger et al. 2009. PubMed ID: 20129283; Table S2 - Berthome et al. 2018. PubMed ID: 30193851). Functional studies found this variant increased sustained sodium channel current resulting in a prolonged depolarization (Wehrens et al. 2003. PubMed ID: 12673799). This variant is reported in 0.0085% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-38645238-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

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

Jul 12, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Long QT syndrome Uncertain:1

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Cardiovascular phenotype Uncertain:1

Jan 05, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1855C>T (p.L619F) alteration is located in exon 12 (coding exon 11) of the SCN5A gene. This alteration results from a C to T substitution at nucleotide position 1855, causing the leucine (L) at amino acid position 619 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Brugada syndrome Other:1

-

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

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

This variant has been reported as associated with Brugada syndrome in the following publications (PMID:12673799;PMID:14998624;PMID:20129283;PMID:22378279). 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	0.11
CardioboostCm	Benign	0.048
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.19
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	.;.;.;.;.;D;.;.;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	.;D;D;D;D;D;D;.;D
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.83	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.76	D
MutationAssessor	Uncertain	2.2	.;M;.;.;.;M;.;.;.
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-2.0	N;N;N;N;N;N;N;N;N
REVEL	Pathogenic	0.73
Sift	Uncertain	0.011	D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.23	T;T;T;T;T;T;T;T;T
Polyphen		0.75	P;P;.;P;.;P;P;.;.
Vest4		0.85
MVP		0.96
MPC		0.97
ClinPred		0.44	T
GERP RS		4.1
Varity_R		0.11
gMVP		0.70

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: rs199473133; hg19: chr3-38645238;