rs199473147

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP2PP3_Moderate

The NM_001099404.2(SCN5A):c.2102C>T(p.Pro701Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000328 in 1,614,038 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P701P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

SCN5A
NM_001099404.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:1O:1

Conservation

PhyloP100: 6.75

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 Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a repeat II (size 270) in uniprot entity SCN5A_HUMAN there are 72 pathogenic changes around while only 4 benign (95%) 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, 0.899

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2 linkuse as main transcript	c.2102C>T	p.Pro701Leu	missense_variant	14/28	ENST00000413689.6
SCN5A	NM_000335.5 linkuse as main transcript	c.2102C>T	p.Pro701Leu	missense_variant	14/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6 linkuse as main transcript	c.2102C>T	p.Pro701Leu	missense_variant	14/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7 linkuse as main transcript	c.2102C>T	p.Pro701Leu	missense_variant	14/28	1	NM_000335.5	A1	Q14524-2

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000883

AC:

AN:

249234

Hom.:

AF XY:

0.0000592

AC XY:

AN XY:

135202

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000319

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:

0.0000974

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000315

AC:

AN:

1461694

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

727132

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000268

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:

0.0000279

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000459

AC:

AN:

152344

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.0000240

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000931

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.000116

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 701 of the SCN5A protein (p.Pro701Leu). This variant is present in population databases (rs199473147, gnomAD 0.03%). This missense change has been observed in individual(s) with long QT syndrome (PMID: 15996170, 17088455, 19716085, 20129283). ClinVar contains an entry for this variant (Variation ID: 67713). 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: 24573164). 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	Aug 08, 2023	Identified in association with cardiac arrhythmia, including LQTS (Tan et al., 2006; Kapplinger et al., 2009; Zellerhoff et al., 2009; Itoh et al., 2016), Brugada syndrome (Kapplinger et al., 2010), and atrial fibrillation (Maekawa et al., 2005); Identified in an individual from a cohort of individuals not selected for cardiomyopathy, arrhythmia, or family history of sudden cardiac death, who underwent exome sequencing and whose follow-up cardiac evaluation was negative for arrhythmia or cardiomyopathy (Ng et al., 2013); Patch clamp studies in HEK293 cells showed that p.(P701L), either expressed alone or co-expressed with wild-type SCN5A channels, had no significant impact on sodium currents compared to wild-type SCN5A channels expressed alone (Hoshi et al., 2014); 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: 19716085, 20129283, 17088455, 15996170, 26332594, 26669661, 28150151, 25904541, 30203441, 19017345, 24573164, 23861362) -
Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	May 18, 2017	We have seen this variant in one patient with Brugada type 1 pattern. Testing was performed at Invitae. Given the weak case data, its presence in individuals with diverse phenotypes, weak functional data, and enriched frequency in population databases, we consider this variant a variant of uncertain significance, likely benign and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Not including our case, the variant has been seen in at least 2 unrelated cases of LQTS and 1 case of atrial fibrillation. It has also been seen in no more than 3 individuals who have had genetic testing for either LQTS, Brugada or cardiomyopathy. No clinical information available on these individuals. There It has not been reported in any confirmed cases of Brugada syndrome. There is weak case data and no segregation data. Tan et al., 2006 (17088455) identified this variant in a 17yo with long QT syndrome and torsade de pointes recruited from the Netherlands. The variant was reported in 1 individual in the Familion compendium, which includes 2500 patients referred for clinical long QT genetic testing (Kapplinger et al 2009). Of note in considering the cases reported by Kapplinger et al (2009) is the lack of phenotypic data on this cohort, the low yield of 36% (vs. 70% in cohorts with firm diagnoses of long QT), and the lack of clarity regarding which variants were seen with another variant (9% of the cohort had multiple variants). Zellerhoff et al. (2009) reports the variant in a 24yo female who has a QTc of 620ms, history of syncope, and atrial flutter/tachycardia. Itoh et al. (2015) reports one family in which two individuals carry this variant. Subjects were recruited from Europe and Japan on the basis that they had a "known pathogenic variant". The authors do not include clinical data and but do include obligate carriers (who may have been unaffected). Some of the authors overlap with the Tan paper, so the case may be redundant. Kapplinger et al. (2010) identified this variant in one patient referred for Brugada syndrome genetic testing. Similar to the group's 2009 paper, there is lack of clinical data. This case may also overlap with the 2009 paper. Maekawa et al.(2005) identified in this variant in one 60yo Japanese patient with atrial fibrillation. They specifically indicate that patients with LQTS and Brugada syndrome were not included in this study. Functional data suggest that the variant does not have an effect on sodium channel activity (Hoshi et al. 2014). The variant is been seen in 26 of 138,593 individuals listed in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. Specifically the variant has been seen in 12 of 17,209 Latino individuals (MAF = 0.03%), 13 of 63,340 European individuals (MAF = 0.01%), and 1 of 12,017 African individuals (0.004%). The average coverage at that site in gnomAD is 75x. Kapplinger et al (2015) reported this variant in one of their healthy controls. -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2016	- -

Cardiac arrhythmia

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 27, 2023	This missense variant replaces proline with leucine at codon 701 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). To our knowledge, functional studies have not been reported for this variant. An experimental study has shown that this variant does not cause significant change in sodium channel activity (PMID: 24573164). This variant has been reported in individuals affected with long QT syndrome (PMID: 17088455), arrhythmia (PMID: 15996170), or Brugada syndrome (PMID: 34856468), in individuals referred for genetic testing for long QT syndrome and Brugada syndrome (PMID: 19716085, 20129283), and in a healthy control individual (PMID: 25904541). This variant has also been identified in 24/280634 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	All of Us Research Program, National Institutes of Health	Jan 11, 2024	This missense variant replaces proline with leucine at codon 701 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). To our knowledge, functional studies have not been reported for this variant. An experimental study has shown that this variant does not cause significant change in sodium channel activity (PMID: 24573164). This variant has been reported in individuals affected with long QT syndrome (PMID: 17088455), arrhythmia (PMID: 15996170), or Brugada syndrome (PMID: 34856468), in individuals referred for genetic testing for long QT syndrome and Brugada syndrome (PMID: 19716085, 20129283), and in a healthy control individual (PMID: 25904541). This variant has also been identified in 24/280634 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. -

Long QT syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Apr 05, 2018

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 29, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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:19716085). 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

0.23

CardioboostArm

Uncertain

0.49

CardioboostCm

Uncertain

0.17

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.49

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.98

M_CAP

Pathogenic

0.74

MetaRNN

Pathogenic

0.90

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

MetaSVM

Pathogenic

1.1

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-7.7

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

REVEL

Pathogenic

0.89

Sift

Uncertain

0.0020

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

Sift4G

Uncertain

0.042

D;D;D;D;T;D;D;T;T

Polyphen

0.99

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

Vest4

0.77

MVP

0.91

MPC

0.98

ClinPred

0.84

GERP RS

4.9

Varity_R

0.66

gMVP

0.97

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

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