rs45609733

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_001099404.2(SCN5A):c.1943C>T(p.Pro648Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000701 in 1,612,474 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 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. P648S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000059 ( 0 hom. )

Consequence

SCN5A
NM_001099404.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:12O:2

Conservation

PhyloP100: 2.58

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant where missense usually causes diseases, SCN5A

BP4

Computational evidence support a benign effect (MetaRNN=0.29274768).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2 linkuse as main transcript	c.1943C>T	p.Pro648Leu	missense_variant	13/28	ENST00000413689.6
SCN5A	NM_000335.5 linkuse as main transcript	c.1943C>T	p.Pro648Leu	missense_variant	13/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6 linkuse as main transcript	c.1943C>T	p.Pro648Leu	missense_variant	13/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7 linkuse as main transcript	c.1943C>T	p.Pro648Leu	missense_variant	13/28	1	NM_000335.5	A1	Q14524-2

Frequencies

GnomAD3 genomes

AF:

0.000177

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.000176

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000403

AC:

AN:

247954

Hom.:

AF XY:

0.0000223

AC XY:

AN XY:

134700

show subpopulations

Gnomad AFR exome

AF:

0.0000651

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:

0.0000804

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000589

AC:

AN:

1460306

Hom.:

Cov.:

AF XY:

0.0000578

AC XY:

AN XY:

726168

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.0000447

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:

0.0000657

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.000177

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.000314

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000172

Hom.:

Bravo

AF:

0.000162

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:12Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 15, 2017	proposed classification - variant undergoing re-assessment, contact laboratory -
Uncertain significance, criteria provided, single submitter	clinical testing	Phosphorus, Inc.	Jan 18, 2022	This missense variant results in an amino acid substitution of proline with leucine at codon 648 of the SCN5A gene. The variant has an entry in ClinVar (48292) NM_000335.5 (SCN5A): c.1943C>T (p.Pro648Leu) and has occurred in GnomAD with a total MAF of 0.0045% and highest MAF of 0.0090% in the European population. This position is not conserved. In silico functional algorithms agreed, with PolyPhen calling it benign, and SIFT tolerated. An in vitro functional study suggests that this variant may impact sodium channel function (PMID: 24613995). The variant has previously been reported in patients referred for long QT syndrome and Brugada syndrome testing (PMID: 20129283, 15840476, 19841300), a patient affected with dilated cardiomyopathy (PMID: 19412328), and a patient that survived an unexplained cardiac arrest (PMID: 28600387). Further evidence is needed to establish whether this variant contributes to disease formation. The variant has therefore been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 08, 2018	Variant summary: SCN5A c.1943C>T (p.Pro648Leu) results in a non-conservative amino acid change located in the Voltage-gated Na+ ion channel, cytoplasmic domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5e-05 in 279294 control chromosomes (gnomAD and publications). The observed variant frequency within African control individuals in the gnomAD database is approximately 2-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in SCN5A causing Arrhythmia phenotype (0.0001), suggesting that the variant could be a benign polymorphism found primarily in populations of African origin. The variant, c.1943C>T, has been reported in the literature in multiple affected individuals diagnosed with varying cardio phenotypes: DCM (Hershberger_2008), LQTS (Kapa_2009, Lieve_2013), Brugada (Kapplinger_2010), and SUDS/SIDS (Dewar_2017, Mellor_2017). Including individuals that have undergone multiple gene panels in which the variant of interest was the only indicated variant to be identified, although cosegregation data was not provided. Therefore, these data do not allow any conclusion about variant significance. Co-occurrences with other pathogenic variant(s) have been reported (MYH7 c.2389G>A, p.Ala797Thr; MYH7 c.1357C>T, p.Arg453Cys; KCNH2 c.1139delT, p.Leu380fsX54). A functional study, Beyder_2014, found slower inactivation of whole-cell Na+ voltage-dependent current by mutant protein in comparison to the wild type, although the residual activity was at approximately 70% of wild-type levels, therefore the correlation of this finding to the established pathophysiology and mechanism of disease is uncertain. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "uncertain significance" (4x) and "likely pathogenic" (1x). Based on the evidence outlined above, the variant was classified as "uncertain significance." -

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 20, 2024	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 648 of the SCN5A protein (p.Pro648Leu). This variant is present in population databases (rs45609733, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of SCN5A-related conditions (PMID: 15840476, 19412328, 19841300, 20129283, 24613995, 26633542, 28600387, 30193851, 31737537). ClinVar contains an entry for this variant (Variation ID: 48292). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on SCN5A function (PMID: 24613995, 32091595, 33131149). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 06, 2023	Published in vitro functional studies using whole-cell voltage clamp analysis suggest faster sodium channel inactivation compared to wild type (Beyder et al., 2014), however, in vivo effect is unknown; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 15840476, 29728395, 32048431, 20129283, 19412328, 25898860, 28600387, 28807990, 26633542, 28150151, 19841300, 25904541, 22337857, 29884292, 22581653, 23631430, 26941339, 30193851, 32091595, 31737537, 34426522, 30203441, 33131149, 24613995) -

Brugada syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Jul 04, 2018

- -

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

Sep 22, 2021

- -

Long QT syndrome

Uncertain:1

Uncertain significance, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Aug 01, 2016

Found in patient having exome sequencing for an unrelated indication. No known history of Long QT syndrome. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 14, 2019

The c.1943C>T (p.P648L) alteration is located in exon 13 (coding exon 12) of the SCN5A gene. This alteration results from a C to T substitution at nucleotide position 1943, causing the proline (P) at amino acid position 648 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Long QT syndrome 3

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues

Feb 08, 2018

- -

Cardiac arrhythmia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jan 10, 2023

This missense variant replaces proline with leucine at codon 648 of the SCN5A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown that this variant may alter sodium channel inactivation kinetics but the change did not appear to be significant (PMID: 24613995). This variant has been reported in an individual affected with long QT syndrome (PMID: 19841300), in an individual affected with familial dilated cardiomyopathy (PMID: 19412328), in individuals affected with unexplained cardiac arrest (PMID: 28600387, 32091595), and in an individual with irritable bowel syndrome, sinus bradycardia and heart block (PMID: 24613995). This variant has been identified in 14/279340 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. -

SUDDEN INFANT DEATH SYNDROME;C1832680:Dilated cardiomyopathy 1E;C1837845:Sick sinus syndrome 1;C1859062:Long QT syndrome 3;C4551804:Brugada syndrome 1

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Brain Gene Registry

Variant classified as Uncertain significance and reported on 12-29-2020 by GeneDx. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. -

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;PMID:19841300). 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

0.074

CardioboostArm

Benign

0.000066

CardioboostCm

Benign

0.0038

BayesDel_addAF

Uncertain

0.015

BayesDel_noAF

Uncertain

-0.020

Cadd

Benign

Dann

Benign

0.34

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.56

FATHMM_MKL

Benign

0.71

M_CAP

Pathogenic

0.29

MetaRNN

Benign

0.29

T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.81

MutationTaster

Benign

1.0

N;N;N;N;N;N;N;N;N;N

PrimateAI

Benign

0.45

PROVEAN

Benign

0.47

N;N;N;N;N;N;N;N;N

REVEL

Uncertain

0.48

Sift

Benign

1.0

T;T;T;T;T;T;T;T;T

Sift4G

Benign

0.85

T;T;T;T;T;T;T;T;T

Polyphen

0.0060

B;B;.;B;.;B;B;.;.

Vest4

0.40

MVP

0.92

MPC

0.36

ClinPred

0.051

GERP RS

3.0

Varity_R

0.027

gMVP

0.65

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over