3-38603722-G-A

Position:

chr3-38603722-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The ENST00000423572.7(SCN5A):c.1880C>T(p.Pro627Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000212 in 1,510,996 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. P627A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

SCN5A
ENST00000423572.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:8

Conservation

PhyloP100: 3.79

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 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SCN5A. . Gene score misZ 2.7504 (greater than the threshold 3.09). Trascript score misZ 4.8279 (greater than threshold 3.09). GenCC has associacion of gene with 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_001099404.2 linkuse as main transcript	c.1880C>T	p.Pro627Leu	missense_variant	12/28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5 linkuse as main transcript	c.1880C>T	p.Pro627Leu	missense_variant	12/28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6 linkuse as main transcript	c.1880C>T	p.Pro627Leu	missense_variant	12/28	5	NM_001099404.2	ENSP00000410257	P4
SCN5A	ENST00000423572.7 linkuse as main transcript	c.1880C>T	p.Pro627Leu	missense_variant	12/28	1	NM_000335.5	ENSP00000398266	A1	Q14524-2

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000170

AC:

AN:

176382

Hom.:

AF XY:

0.00

AC XY:

AN XY:

93246

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000464

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:

0.0000233

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000199

AC:

AN:

1358820

Hom.:

Cov.:

AF XY:

0.0000121

AC XY:

AN XY:

663670

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000336

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000146

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000226

Gnomad4 OTH exome

AF:

0.0000179

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152176

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000604

ExAC

AF:

0.00000846

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 31, 2017	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 1 paper weak segregation data -
Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jun 15, 2013	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Pro627Leu (P627L; c.1880 C>T) in the SCN5A gene This variant has previously been reported in one unrelated individual with LQTS, with weak segregation data. Blaufox et al. (2012) found Pro627Leu in an LQT3 proband with a prolonged QTc interval. It was also present in the proband’s mother, who likewise had a prolonged QTc interval. Either this proband or the proband’s mother had suffered an aborted sudden cardiac death event (the language in the paper is unclear). Their ancestry is not specified. The study included 81% Caucasian, 11% African-American, and 8% Hispanic families. If the family was Hispanic, there is less ancestry-matched control data available. Variation at several nearby residues has been associated with arrhythmia syndromes, suggesting the functional importance of this protein region: Leu618Phe (LQT3), Leu619Phe (LQT3/Brugada), Arg620Cys (Brugada), Thr632Met (Brugada) (UniProtKB; IRCCS Fondazione Salvatore Maugeri database; testing report referencing HGMD database). This is a conservative amino acid change, resulting in the replacement of a nonpolar, sterically-constrained proline with a nonpolar leucine residue. The proline at this location is highly conserved across mammalian species. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “probably damaging”. In total the variant has not been seen in >6500 published controls and individuals from publicly available population datasets. This variant is not listed in the NHLBI Exome Sequencing Project dataset (http://evs.gs.washington.edu/EVS/), which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals. (Our patient’s ancestry is Hispanic.) No variation at this residue is found in dbSNP (http://www.ncbi.nlm.nih.gov/projects/SNP). It is not found in 1000 genomes (http://browser.1000genomes.org/Homo_sapiens/Search/New?db=core) as of December 2, 2012. Blaufox et al. (2012) did not report controls. -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 15, 2024	Reported in a proband with sudden death and also identified in this individual's mother; the mother was reported to have QTc prolongation, although no additional details were provided (PMID: 22360817); Reported in an individual with HCM, severe right ventricular hypertrophy, and no noted arrhythmia who was found to harbor several additional cardiogenetic variants in genes associated with her phenotype (PMID: 28323875); Not observed at significant frequency in large population cohorts (gnomAD); Functionals studies demonstrated that p.(P627L) expressed in HEK-293 cells resulted in an electrophysiological phenotype similar to the wildtype; nevertheless, it is not clear how well these studies reproduce in vivo conditions (PMID: 25904541); 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: 27566755, 22360817, 28323875, 25904541) -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 10, 2023	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 627 of the SCN5A protein (p.Pro627Leu). This variant is present in population databases (rs778522112, gnomAD 0.005%). This missense change has been observed in individual(s) with clinical features of SCN5A-related conditions (PMID: 22360817, 28323875). ClinVar contains an entry for this variant (Variation ID: 201577). 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 tolerated. Experimental studies have shown that this missense change does not substantially affect SCN5A function (PMID: 25904541). 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	Sep 23, 2024	This missense variant replaces proline with leucine at codon 627 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). A functional study has indicated that this missense does not affect sodium channel function (PMID: 25904541). This variant has been reported in a few individuals affected with long QT syndrome (PMID: 22360817, 27566755), in an individual affected with idiopathic dilated cardiomyopathy (Rodriguez-Garcia et al., 2011), and in two individuals affected with hypertrophic cardiomyopathy who also carried another pathogenic variant in the DSP or MYH7 genes (PMID: 28323875). This variant has been identified in 3/176382 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 24, 2023	This missense variant replaces proline with leucine at codon 627 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). A functional study has indicated that this missense does not affect sodium channel function (PMID: 25904541). This variant has been reported in a few individuals affected with long QT syndrome (PMID: 22360817, 27566755), in an individual affected with idiopathic dilated cardiomyopathy (Rodriguez-Garcia et al., 2011), and in two individuals affected with hypertrophic cardiomyopathy who also carried another pathogenic variant in the DSP or MYH7 genes (PMID: 28323875). This variant has been identified in 3/176382 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;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

Oct 12, 2021

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 22, 2020

The p.P627L variant (also known as c.1880C>T), located in coding exon 11 of the SCN5A gene, results from a C to T substitution at nucleotide position 1880. The proline at codon 627 is replaced by leucine, an amino acid with similar properties. This alteration was detected in an individual with a QTc interval of 427ms and in her mother, who was reported to have a prolonged QTc interval (Blaufox AD et al. Am. J. Cardiol., 2012 May;109:1459-65). In addition, this alteration has been reported in a cohort of long QT syndrome patients (Wilde AA et al. Circulation, 2016 Sep;134:872-82), as well as in an individual with hypertrophic cardiomyopathy who also had variants in other cardiac-related genes (Guo X et al. PLoS ONE, 2017 Mar;12:e0174118). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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

Benign

0.068

CardioboostCm

Benign

0.0011

BayesDel_addAF

Uncertain

0.098

BayesDel_noAF

Uncertain

0.040

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.68

.;.;.;.;.;D;.;.;.

Eigen

Benign

0.17

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.89

.;D;D;D;D;D;D;.;D

M_CAP

Pathogenic

0.40

MetaRNN

Uncertain

0.56

D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.48

MutationAssessor

Benign

1.4

.;L;.;.;.;L;.;.;.

MutationTaster

Benign

0.99

D;D;D;D;D;D;D;D;D;D

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-3.2

D;D;D;D;D;D;D;D;D

REVEL

Uncertain

0.50

Sift

Benign

0.11

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

Sift4G

Benign

0.12

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

Polyphen

0.91

P;P;.;P;.;D;P;.;.

Vest4

0.45

MutPred

0.23

Loss of glycosylation at P627 (P = 0.0692);Loss of glycosylation at P627 (P = 0.0692);Loss of glycosylation at P627 (P = 0.0692);Loss of glycosylation at P627 (P = 0.0692);Loss of glycosylation at P627 (P = 0.0692);Loss of glycosylation at P627 (P = 0.0692);Loss of glycosylation at P627 (P = 0.0692);Loss of glycosylation at P627 (P = 0.0692);Loss of glycosylation at P627 (P = 0.0692);

MVP

0.80

MPC

0.55

ClinPred

0.84

GERP RS

4.1

Varity_R

0.069

gMVP

0.74

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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