rs199473335

chr3-38550411-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001099404.2(SCN5A):c.5961C>A(p.Asn1987Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,579,164 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:10 O:1
• Conservation: PhyloP100: 1.92

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 1 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=0.24517506).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2	c.5961C>A	p.Asn1987Lys	missense_variant	28/28	ENST00000413689.6
SCN5A	NM_000335.5	c.5958C>A	p.Asn1986Lys	missense_variant	28/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.5961C>A	p.Asn1987Lys	missense_variant	28/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.5958C>A	p.Asn1986Lys	missense_variant	28/28	1	NM_000335.5	A1

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152254 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00000882 AC: 2 AN: 226736 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 121278

Gnomad AFR exome AF: 0.00

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: 0.0000193

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000273 AC: 39 AN: 1426910 Hom.: 0 Cov.: 31 AF XY: 0.0000284 AC XY: 20 AN XY: 704122

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000255

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000302

Gnomad4 OTH exome AF: 0.0000849

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152254 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74382

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

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: 0.0710 Hom.: 823

Bravo AF: 0.0000151

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2017	The N1987K variant in the SCN5A gene has been reported previously (as N1986K using alternate nomenclature) in a father and son with atrial fibrillation (Ellinor et al., 2008). Additionally, expression of N1986K in Xenopus oocytes revealed a hyperpolarizing shift in channel steady-state inactivation (Ellinor et al., 2008). The N1987K variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The N1987K variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret N1987K as a variant of uncertain significance -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 23, 2018	The SCN5A c.5961C>A; p.Asn1987Lys was found in the heterozygous state in a father/son pair who were diagnosed with atrial fibrillation with sick sinus syndrome and lone atrial fibrillation, respectively (Ellinor 2008). Functional studies showed that Xenopus oocytes expressing this variant protein exhibited a hyperpolarizing shift in sodium channel steady-state inactivation, but normal voltage-dependent activation and time course of recovery from inactivation (Ellinor 2008). This variant is listed in the genome Aggregation Database (gnomAD) with an overall population frequency of 0.001% (identified on 3 out of 254,540 chromosomes), and is classified as a variant of unknown significance in ClinVar (ID: 30045). The asparagine at position 1987 is highly conserved, considering 9 species, and computational analyses of the effects of the p.Asn1987Lys variant on protein structure and function do not predict a deleterious effect (SIFT: tolerated, PolyPhen-2: benign). Based on the available information, the clinical significance of the p.Asn1987Lys variant cannot be determined. -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Cardiac arrhythmia Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 05, 2022	This missense variant replaces asparagine with lysine at codon 1987 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 3/258138 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	Dec 03, 2022	This missense variant replaces asparagine with lysine at codon 1987 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 3/258138 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. -

Atrial fibrillation Uncertain:1 Other:1

Uncertain significance, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
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 Atrial fibrillation in the following publications (PMID:18088563). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

Atrial fibrillation, familial, 10 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2008

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 14, 2014

The Asn1987Lys variant in SCN5A has been reported in 1 individual with atrial fi brillation and was found to segregate with disease in 1 affected relative (Ellin or 2008). This variant has also been identified in 1/8344 European American chro mosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/ ; dbSNP rs199473335). Functional studies suggest this variant impact the protein (Ellinor 2008), though these in vitro studies may not accurately represent biol ogical function. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, add itional data is needed to fully assess the clinical significance of the Asn1987L ys variant. -

Brugada syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 14, 2022

This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 1987 of the SCN5A protein (p.Asn1987Lys). This variant is present in population databases (rs199473335, gnomAD 0.003%). This missense change has been observed in individual(s) with atrial fibrillation, dilated cardiomyopathy, and/or hypertrophic cardiomyopathy (PMID: 18088563, 30847666). This variant is also known as N1986K. ClinVar contains an entry for this variant (Variation ID: 30045). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects SCN5A function (PMID: 18088563). 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. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 23, 2020

The c.5961C>A (p.N1987K) alteration is located in exon 28 (coding exon 27) of the SCN5A gene. This alteration results from a C to A substitution at nucleotide position 5961, causing the asparagine (N) at amino acid position 1987 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
CardioboostArm	Benign	0.000051
CardioboostCm	Benign	0.0045
BayesDel_addAF	Uncertain	0.077	D
BayesDel_noAF	Benign	-0.10
Cadd	Benign	20
Dann	Benign	0.93
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.0052
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.25	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.30	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	1.3	N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.37
Sift	Benign	1.0	T;T;T;T;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T;T
Polyphen		0.063	B;B;.;B;.;P;D;.;.
Vest4		0.42
MutPred		0.75		.;.;Gain of ubiquitination at N1987 (P = 0.0022);.;.;Gain of ubiquitination at N1987 (P = 0.0022);.;.;.;
MVP		0.80
MPC		1.5
ClinPred		0.27	T
GERP RS		5.0
Varity_R		0.079
gMVP		0.30

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: rs199473335; hg19: chr3-38591902;