rs199473147

Variant names:

• chr3-38597889-G-A
• rs199473147
• NM_001099404.2:c.2102C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-38597889-G-A
• chr3-38597889-G-C
• chr3-38597889-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:7 B:1 O:1
• Conservation: PhyloP100: 6.75
• Publications: 12 publications found

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 Gene-Disease associations (from GenCC):

• Brugada syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Brugada syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Laboratory for Molecular Medicine, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 1E

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial long QT syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• long QT syndrome 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• sick sinus syndrome 1

  Inheritance: AD, AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• progressive familial heart block, type 1A

  Inheritance: SD, AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp
• atrial standstill

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial atrial fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial sick sinus syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• paroxysmal familial ventricular fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• progressive familial heart block

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• short QT syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.899

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.2102C>T	p.Pro701Leu	missense_variant	Exon 14 of 28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.2102C>T	p.Pro701Leu	missense_variant	Exon 14 of 28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.2102C>T	p.Pro701Leu	missense_variant	Exon 14 of 28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.2102C>T	p.Pro701Leu	missense_variant	Exon 14 of 28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152226 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.0000883 AC: 22 AN: 249234 AF XY: 0.0000592

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000974

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000315 AC: 46 AN: 1461694 Hom.: 0 Cov.: 31 AF XY: 0.0000289 AC XY: 21 AN XY: 727132

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.000268 AC: 12 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000279 AC: 31 AN: 1111860

Other (OTH) AF: 0.0000331 AC: 2 AN: 60374

GnomAD4 genome AF: 0.0000459 AC: 7 AN: 152344 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74500

African (AFR) AF: 0.0000240 AC: 1 AN: 41580

American (AMR) AF: 0.0000653 AC: 1 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000822 Hom.: 0

Bravo AF: 0.0000491

ExAC AF: 0.000116 AC: 14

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4

May 18, 2017

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: provider interpretation

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. -

Nov 01, 2016

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 08, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 Brugada syndrome and/or long QT syndrome (PMID: 15996170, 17088455, 19716085, 20129283, 34856468). 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. -

Cardiac arrhythmia Uncertain:2

Feb 13, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. A functional 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) and Brugada syndrome (PMID: 34856468), as well as 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. -

Jul 29, 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 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. A functional 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) and Brugada syndrome (PMID: 34856468), as well as 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. -

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 Pathogenic:1

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PP3_Moderate+PP2+PS4_Moderate -

Long QT syndrome Uncertain:1

Apr 05, 2018

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Cardiovascular phenotype Benign:1

Mar 29, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

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 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	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	.;.;.;.;.;D;.;.;.
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	.;D;D;D;D;D;D;.;D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	.;H;.;.;.;H;.;.;.
PhyloP100		6.8
PrimateAI	Uncertain	0.64	T
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	D
GERP RS		4.9
Varity_R		0.66
gMVP		0.97
Mutation Taster		=0/100	disease causing

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

Other links and lift over

dbSNP: rs199473147; hg19: chr3-38639380;