rs137854602

chr3-38555664-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_001099404.2(SCN5A):c.4534C>T(p.Arg1512Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,613,190 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1512L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:8 O:1
• Conservation: PhyloP100: 1.03

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a repeat IV (size 297) in uniprot entity SCN5A_HUMAN there are 117 pathogenic changes around while only 4 benign (97%) 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, 0.955
• PP5: Variant 3-38555664-G-A is Pathogenic according to our data. Variant chr3-38555664-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 9380.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=7, Likely_pathogenic=5, not_provided=1}. Variant chr3-38555664-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2	c.4534C>T	p.Arg1512Trp	missense_variant	26/28	ENST00000413689.6
SCN5A	NM_000335.5	c.4531C>T	p.Arg1511Trp	missense_variant	26/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.4534C>T	p.Arg1512Trp	missense_variant	26/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.4531C>T	p.Arg1511Trp	missense_variant	26/28	1	NM_000335.5	A1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152134 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

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: 0.00

GnomAD3 exomes AF: 0.0000557 AC: 14 AN: 251272 Hom.: 0 AF XY: 0.0000589 AC XY: 8 AN XY: 135804

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000290

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: 0.0000176

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1461056 Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13 AN XY: 726796

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000989

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152134 Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2 AN XY: 74316

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

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: 0.00

Alfa AF: 0.0000425 Hom.: 0

Bravo AF: 0.0000604

ExAC AF: 0.0000741 AC: 9

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:8 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:3 Uncertain:3 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 04, 2023	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1512 of the SCN5A protein (p.Arg1512Trp). This variant is present in population databases (rs137854602, gnomAD 0.03%). This missense change has been observed in individuals with clinical features of Brugada syndrome (PMID: 10690282, 15851227, 20110800, 20486126, 22840528, 24529773, 25650408, 26111534). ClinVar contains an entry for this variant (Variation ID: 9380). 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 disruptive. Experimental studies have shown that this missense change affects SCN5A function (PMID: 10690282, 10727653). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
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:10690282;PMID:10727653;PMID:15851227;PMID:19251209;PMID:19841300;PMID:20129283). -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 28, 2020	The SCN5A c.4534C>T; p.Arg1512Trp variant (rs137854602) is reported in the literature in multiple individuals affected with Brugada syndrome, cardiac conduction disease, or sudden unexpected death (Cheng 2011, Chiang 2015, Crotti 2012, Deschenes 2000, Meregalli 2009, Rook 1999), although it has also been observed in a healthy control (Ackerman 2004, Kapplinger 2010). This variant is found in the general population with an overall allele frequency of 0.006% (14/251272 alleles) in the Genome Aggregation Database and is reported in ClinVar (Variation ID: 9380). The arginine at codon 1512 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Functional analyses consistently indicate a slower recovery from inactivation (Deschenes 2000, Rook 1999, Zheng 2016), but also report conflicting mechanisms. While one report indicates a gain-of-function mechanism marked by increased excitability and lower action potential threshold (Rook 1999), several other studies report loss-of-function characterized by reduced peak sodium current (Deschenes 2000, Zheng 2016), which is exacerbated under acidosis conditions (Zheng 2016). While it is possible that the p.Arg1512Trp variant is associated with disease with reduced penetrance, due to incomplete and conflicting information, its clinical significance remains uncertain at this time. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 15, 2022	PP3, PM6 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 14, 2023	Reported in multiple individuals with Brugada syndrome or sudden unexplained nocturnal death (SUND) (Cheng et al., 2011; Crotti et al., 2012; Liu et al., 2014; Meregalli et al., 2009; Deschnes et al., 2000; Berthome et al., 2019; LeScouarnec et al., 2015; Zhang et al., 2021), and reported in at least one healthy control individual (Kapa et al., 2009; Kapplinger et al., 2010; Crotti et al., 2012; Ackerman et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect (Deschenes et al., 2000; Rook et al., 1999; Zheng et al., 2016; Hu et al., 2021), however, they propose different mechanisms of disease, and additional studies are needed to validate the functional effect of this variant in vivo; This variant is associated with the following publications: (PMID: 28518168, 26111534, 19251209, 34649698, 15851227, 27281089, 19841300, 22840528, 24529773, 10727653, 33221895, 33535892, 30662450, 31564432, 32268277, 30193851, 33131149, 25650408, 20486126, 20129283, 10690282, 20110800, 35911527, 36516610, 36435694, 34461752, 34546463, 36007526, 35124229) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 06, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 14, 2023	This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant has been identified in multiple individuals with clinical features of Brugada syndrome, and appeared to occur de novo in an individual with sudden unexplained nocturnal death syndrome (SUNDS). In some published literature, this variant is referred to as c.4372C>T, p.Arg1458Trp. Computational tools predict that this variant is damaging. -

Brugada syndrome 1 Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 1999	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Medical Genetics Ghent, University of Ghent	Jan 01, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	Aug 30, 2018	This variant has been previously reported by multiple clinical labs as pathogenic or likely pathogenic according to the ClinVar database. One clinical lab reports p.Arg1512Trp as a variant of uncertain significance. Additionally, there multiple reports in the literature of the variant in patients diagnosed with Brugada Syndrome and arrhythmias (PMID: 10690282, 10727653, 19251209, 20110800, 26111534, 27281089). This variant was identified in a healthy adult in one publication (PMID: 15851227). Functional studies characterizing the effect of the variant on protein function demonstrates altered channel gating dynamics relative to the reference allele. Deschenes et al. demonstrated that p.Arg1512Trp results in loss of function, producing a slowing of both inactivation and recovery from inactivation (PMID: 10727653). Rook et al. found p.Arg1512Trp resulted in moderate kinetic alterations including a negative voltage shift of steady-state activation and inactivation curves (PMID: 10690282). More recently, Zheng et al. identified a de novo p.Arg1512Trp variant in a 38 year old Chinese patient with tachypnea and sudden unexplained noctural death (SUNDS)(PMID: 27281089). These authors also demonstrated a more deleterious effect of the variant under slightly acidic conditions (pH 7.0 versus pH 7.4). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.004% (12/246090) and thus is presumed to be rare. The p.Arg1512Trp variant is a non-conservative amino acid substitution predicted to be damaging by multiple in silico tools and the amino acid residue is highly conserved among eukaryotes. Based on the available evidence, the c.4534C>T (p.Arg1512Trp) variant is classified as likely pathogenic. -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 29, 2019	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg1512Trp variant in SCN5A has been reported in 7 individuals with features of arrhythmia, sudden death, Brugada syndrome and/or LQTS (Rook 1999, Deschênes 2000, Meregalli 2009, Cheng 2011, Crotti 2012, Chiang 2015) and in 1 individual with infantile onset of LV dysfunction (LMM data). It has been identified in 9/33552 Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs137854602). This variant is present in ClinVar (Variation ID: 9380). In vitro functional studies provide some evidence that the variant may impact protein function (Rook 1999, Deschênes 2000, Zheng 2016). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Arg1512Trp variant is uncertain. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 15, 2023	Variant summary: SCN5A c.4534C>T (p.Arg1512Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.3e-05 in 255630 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SCN5A causing Brugada Syndrome (6.3e-05 vs 0.00017), allowing no conclusion about variant significance. c.4534C>T has been reported in the literature in individuals affected with Brugada Syndrome and sudden death (eg. Rook_1999, Deschenes_2000, Cheng_2011, Meregalli_2009, Chiang_2016), including one report in a healthy individual (Crotti_2012), a patient who carried a known pathogenic SCN5A variant (Zhang_2022), in a 38 year old with sudden death in whom the variant was reported to be de novo (Zheng_2016), and from an exome sequencing trio inherited from the mother (Kingsmore_2019). These data indicate that the variant may be associated with disease. Functional studies have demonstrated various damaging impacts of the variant. These impacts include slowed inactivation and recovery from inactivation (Deschenes_2000), a moderate alteration in kinetics including a negative voltage shift of steady-state activation and inactivation curves (Rook_1999) and a more damaging effect was seen under slightly acidic conditions (Zheng_2016). However, it is unclear what how well these impacts represent the biological impact of the variant. The following publications have been ascertained in the context of this evaluation (PMID: 15851227, 14961552, 20129283, 20486126, 22840528, 24529773, 10727653, 19251209, 10690282, 26111534, 27281089, 31564432, 34649698, 20110800). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments: four submitters classified the variant as VUS while four classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS - possibly pathogenic. -

Primary familial hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Blueprint Genetics

Jul 18, 2014

- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 11, 2022

The c.4534C>T (p.R1512W) alteration is located in exon 26 (coding exon 25) of the SCN5A gene. This alteration results from a C to T substitution at nucleotide position 4534, causing the arginine (R) at amino acid position 1512 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Cardiac arrhythmia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jun 16, 2023

This missense variant replaces arginine with tryptophan at codon 1512 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). Functional studies have shown that this variant results in altered cardiac sodium channel characteristics, reduced peak sodium current, and decreased cell surface expression of the channel (PMID: 10690282, 10727653, 27281089, 33535892). This variant has been reported in individuals affected with Brugada syndrome (PMID: 10690282, 10727653, 19251209, 20486126, 25650408, 30193851, 36516610, 37061847), sudden death (PMID: 20110800, 24529773, 26111534), as well as in healthy control individuals (PMID: 15851227,19841300, 20129283, 22840528). This variant has been identified in 14/251272 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
CardioboostArm	Uncertain	0.87
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.49
Cadd	Benign	22
Dann	Uncertain	1.0
Eigen	Uncertain	0.34
Eigen_PC	Benign	0.14
FATHMM_MKL	Benign	0.67	D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	0.97	A;A;A;A;A;A;A;A;A;A
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-7.4	D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;.;D;.;D;D;.;.
Vest4		0.94
MVP		0.98
MPC		1.5
ClinPred		0.99	D
GERP RS		1.6
Varity_R		0.76
gMVP		0.94

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: rs137854602; hg19: chr3-38597155; COSMIC: COSV61119646; COSMIC: COSV61119646;