rs137854602

Variant names:

• chr3-38555664-G-A
• rs137854602
• NM_001099404.2:c.4534C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-38555664-G-A
• chr3-38555664-G-C

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PS3 PP3_Strong PP5

The NM_000335.5(SCN5A):​c.4531C>T​(p.Arg1511Trp) 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). ClinVar reports functional evidence for this variant: "SCV000996193: 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).; SCV000545007: Experimental studies have shown that this missense change affects SCN5A function (PMID:10690282, 10727653).; SCV004241184: 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). PMID:15851227, 20486126, 20110800, 26111534, 22840528, 10727653, 20129283, 31564432, 24529773, 19251209, 37061847, 37547970, 10690282, 14961552, 34649698, 27281089". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1511L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: SCN5A NM_000335.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:10 U:8 O:1
• Conservation: PhyloP100: 1.03
• Publications: 44 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: Orphanet, ClinGen
• Brugada syndrome 1

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

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

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

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

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

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• progressive familial heart block, type 1A

  Inheritance: AD, SD Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Ambry Genetics
• sick sinus syndrome 1

  Inheritance: AR, AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• 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
• congenital heart disease

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

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000996193: 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).; SCV000545007: Experimental studies have shown that this missense change affects SCN5A function (PMID: 10690282, 10727653).; SCV004241184: 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). PMID: 15851227, 20486126, 20110800, 26111534, 22840528, 10727653, 20129283, 31564432, 24529773, 19251209, 37061847, 37547970, 10690282, 14961552, 34649698, 27281089
• 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 VariationId is 9380.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000335.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN5A	NM_001099404.2	MANE Plus Clinical	c.4534C>T	p.Arg1512Trp	missense	Exon 26 of 28	NP_001092874.1	H9KVD2
	SCN5A	NM_000335.5	MANE Select	c.4531C>T	p.Arg1511Trp	missense	Exon 26 of 28	NP_000326.2
	SCN5A	NM_198056.3		c.4534C>T	p.Arg1512Trp	missense	Exon 26 of 28	NP_932173.1	Q14524-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN5A	ENST00000413689.6	TSL:5 MANE Plus Clinical	c.4534C>T	p.Arg1512Trp	missense	Exon 26 of 28	ENSP00000410257.1	H9KVD2
	SCN5A	ENST00000423572.7	TSL:1 MANE Select	c.4531C>T	p.Arg1511Trp	missense	Exon 26 of 28	ENSP00000398266.2	Q14524-2
	SCN5A	ENST00000333535.9	TSL:1	c.4534C>T	p.Arg1512Trp	missense	Exon 26 of 28	ENSP00000328968.4	Q14524-1

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

GnomAD2 exomes AF: 0.0000557 AC: 14 AN: 251272 AF XY: 0.0000589

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 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

African (AFR) AF: 0.0000299 AC: 1 AN: 33454

American (AMR) AF: 0.000201 AC: 9 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

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

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86160

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5338

European-Non Finnish (NFE) AF: 0.00000989 AC: 11 AN: 1111866

Other (OTH) AF: 0.0000497 AC: 3 AN: 60314

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

African (AFR) AF: 0.00 AC: 0 AN: 41426

American (AMR) AF: 0.0000654 AC: 1 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000425 Hom.: 0

Bravo AF: 0.0000604

ExAC AF: 0.0000741 AC: 9

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
4	3	-	not provided (8)
5	1	-	Brugada syndrome 1 (6)
1	-	-	Brugada syndrome (shorter-than-normal QT interval) (1)
-	1	-	Cardiac arrhythmia (1)
-	1	-	Cardiovascular phenotype (1)
-	1	-	not specified (1)
-	1	-	Primary familial hypertrophic cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Pathogenic	0.90	D
Eigen	Uncertain	0.34
Eigen_PC	Benign	0.14
FATHMM_MKL	Benign	0.67	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		1.0
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-7.4	D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	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
Mutation Taster		=1/99	disease causing (ClinVar)

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