rs150264233

chr3-38550661-G-Achr3-38550661-G-Cchr3-38550661-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 6P and 3B. PM1 PM2 PP2 PP3 BP4_Moderate BP6

The NM_001099404.2(SCN5A):c.5711C>T(p.Ser1904Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000737 in 1,614,054 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1904W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000041 (0 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:7 O:1
• Conservation: PhyloP100: 8.13

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 3 ACMG points.

• PM1: In a helix (size 30) in uniprot entity SCN5A_HUMAN there are 7 pathogenic changes around while only 2 benign (78%) in NM_001099404.2
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SCN5A
• PP3: Multiple lines of computational evidence support a deleterious effect 11: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Dann, Eigen, M_CAP, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when CardioboostArm, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.16239089).
• BP6: Variant 3-38550661-G-A is Benign according to our data. Variant chr3-38550661-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 48310.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, not_provided=1, Uncertain_significance=2, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2	c.5711C>T	p.Ser1904Leu	missense_variant	28/28	ENST00000413689.6
SCN5A	NM_000335.5	c.5708C>T	p.Ser1903Leu	missense_variant	28/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.5711C>T	p.Ser1904Leu	missense_variant	28/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.5708C>T	p.Ser1903Leu	missense_variant	28/28	1	NM_000335.5	A1

Frequencies

GnomAD3 genomes AF: 0.000387 AC: 59 AN: 152260 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00135

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: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000132 AC: 33 AN: 249274 Hom.: 0 AF XY: 0.0000961 AC XY: 13 AN XY: 135226

Gnomad AFR exome AF: 0.00181

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000410 AC: 60 AN: 1461676 Hom.: 0 Cov.: 32 AF XY: 0.0000344 AC XY: 25 AN XY: 727114

Gnomad4 AFR exome AF: 0.00149

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000663

GnomAD4 genome AF: 0.000387 AC: 59 AN: 152378 Hom.: 0 Cov.: 33 AF XY: 0.000268 AC XY: 20 AN XY: 74508

Gnomad4 AFR AF: 0.00135

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: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000929 Hom.: 0

Bravo AF: 0.000453

ESP6500AA AF: 0.00236 AC: 10

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000190 AC: 23

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2 Benign:7 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1 Other:1

not provided, no classification provided	literature only	Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	-	This variant has been reported in the following publications (PMID:18708744;PMID:20129283;PMID:22378279;PMID:22426227). -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 23, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 13, 2023	LQTS is caused by gain of function variants in the SCN5A channel (NaV1.5), while Brugada syndrome is caused by loss of function variants; as this variant has been identified in individuals with diseases that have different mechanisms of pathogenicity, its clinical significance is uncertain; 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: 22378279, 20129283, 25904541, 28988457, 30847666, 25637381, 22426227, 26159999, 26332594, 24892747, 27435932, 29728395, 26746457, 34021086, 30153324, 21167176, 18708744, 30203441, Tomaselli2023[Functional], 35662881, 24055113) -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 23, 2022	Variant summary: SCN5A c.5711C>T (p.Ser1904Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00017 in 283812 control chromosomes (gnomAD, Bankston_2007, Kapplinger_2010, Kapplinger_2015), predominantly at a frequency of 0.0017 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 68 fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN5A causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.5711C>T has been reported in at least one individual with LQTS and segregated with symptoms of disease in two family members, however only a subset of LQTS-associated genes were sequenced in these individuals (Bankston_2007). In addition, the variant has been reported in at least one individual affected with SIDS (Methner_2017). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. Several publications report experimental evidence evaluating an impact on protein function. These studies report that the variant disrupts sodium channel gate inactivation and promotes late Na+ channel currents by increasing the propensity of the channel to reopen during prolonged depolarization (Bankston_2007, Glaaser_2012). Another study reports that the variant may have a more severe electrophysiological impact in certain tissue types, as the effect in Purkinje fiber cells was more significant than that observed in a ventricular myocyte model (Iyer_2014). A recent study showed that the variant had had reduced affinity for Calmodulin binding compared to wildtype (Kang_2021). These in-vitro studies do not allow convincing conclusions about the variant effect, however, as the variant does not appear to alter the overall function of the sodium channels and it is unclear how these findings would translate in-vivo. Eight ClinVar submitters have assessed the variant since 2014: two classified the variant as of uncertain significance, four as likely benign, one as benign and one as pathogenic. Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 05, 2020	The p.Ser1904Leu variant in SCN5A has been reported in several individuals with a range of cardiac manifestations (Bankston 2007 PMID: 18708744, Kapplinger 2010 PMID: 20129283, Methner 2016 PMID: 27435932, LMM data). However, this variant has also been identified in 0.17% (42/24204) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency is inconsistent with the reported prevalence of SCN5A-associated disease. This variant has also been reported in ClinVar (Variation ID: 48310). Computational prediction tools and conservation analyses predict an impact to the protein and in vitro studies suggest that the p.Ser1904Leu variant may impact protein function (Bankston 2007 PMID: 18708744, Glaaser 2012 PMID: 22426227, Kapplinger 2010 PMID: 20129283). However, this in vitro assay may not accurately represent biological function. In summary, because of the frequency, this variant is classified as likely benign. ACMG/AMP Criteria applied: PP3, PS4_Supporting, BS1. -

Death in infancy Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Forensic Genetics Laboratory, Harris County Institute of Forensic Sciences

Mar 27, 2015

- -

Brugada syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Long QT syndrome Benign:1

Likely benign, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 18, 2019

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. -

Cardiac arrhythmia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Nov 24, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
CardioboostArm	Benign	0.021
CardioboostCm	Uncertain	0.82
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.58
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Pathogenic	0.83	D
MetaRNN	Benign	0.16	T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-5.5	D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.010	D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;.;D;.;D;D;.;.
Vest4		0.53
MVP		0.96
MPC		1.3
ClinPred		0.74	D
GERP RS		4.9
Varity_R		0.90
gMVP		0.95

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: rs150264233; hg19: chr3-38592152;