rs199473145

Variant names:

• chr3-38597925-C-G
• rs199473145
• NM_001099404.2:c.2066G>C
• SCN5A p.Arg689Pro

Your query was ambiguous. Multiple possible variants found:

• chr3-38597925-C-G
• chr3-38597925-C-T

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+3 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 3 classification points (ACMG Germline Pathogenicity v2019). PM2PP3

The NM_000335.5(SCN5A):c.2066G>C (p.Arg689Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant has a gnomAD grpmax filtering allele frequency (95% CI) of 0.0000009, indicating it is observed in the general population. Note: a gnomAD entry for this variant shows a statistical allele-bias signature, consistent with mosaic/somatic contamination (e.g. age-related clonal hematopoiesis) rather than true inherited population frequency — this frequency should not be read as evidence of a common, benign germline variant. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (★★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R689C: Uncertain_significance (ClinVar VariationId 67709, 2 stars); p.R689H: Uncertain_significance (ClinVar VariationId 67710, 2 stars)

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SCN5A NM_000335.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.183
• Publications: 18 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 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• dilated cardiomyopathy 1E

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• long QT syndrome 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• SCN5A-related cardiac rhythm disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• 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
• Brugada syndrome

  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, G2P
• congenital heart disease

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 3 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.0000009 — very rare for AD+AR gene (base 0.0001, raised to 0.000152 by highest known P/LP ClinVar AF 0.000152) — PM2 moderate.
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — supporting evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Supporting).

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	SCN5A NM_001099404.2	MANE Plus Clinical	c.2066G>C p.Arg689Pro	missense	Exon 14 of 28	Prot: NP_001092874.1 UniProt:
	SCN5A NM_000335.5	MANE Select	c.2066G>C p.Arg689Pro	missense	Exon 14 of 28	Prot: NP_000326.2
	SCN5A NM_198056.3		c.2066G>C p.Arg689Pro	missense	Exon 14 of 28	Prot: NP_932173.1 UniProt:

SCN5A NM_001099404.2

MANE Plus Clinical

HGVSc / HGVSpc.2066G>Cp.Arg689Pro

Exon rankExon 14 of 28

missense

Prot: NP_001092874.1UniProt: H9KVD2

SCN5A NM_000335.5

MANE Select

HGVSc / HGVSpc.2066G>Cp.Arg689Pro

Exon rankExon 14 of 28

missense

Prot: NP_000326.2

SCN5A NM_198056.3

HGVSc / HGVSpc.2066G>Cp.Arg689Pro

Exon rankExon 14 of 28

missense

Prot: NP_932173.1UniProt: Q14524-1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	SCN5A ENST00000413689.6	TSL:5MANE Plus Clinical	c.2066G>C p.Arg689Pro	missense	Exon 14 of 28	Prot: ENSP00000410257.1 UniProt:
	SCN5A ENST00000423572.7	TSL:1MANE Select	c.2066G>C p.Arg689Pro	missense	Exon 14 of 28	Prot: ENSP00000398266.2 UniProt:
	SCN5A ENST00000333535.9	TSL:1	c.2066G>C p.Arg689Pro	missense	Exon 14 of 28	Prot: ENSP00000328968.4 UniProt:

SCN5A ENST00000413689.6

TSL:5MANE Plus Clinical

HGVSc / HGVSpc.2066G>Cp.Arg689Pro

Exon rankExon 14 of 28

missense

Prot: ENSP00000410257.1UniProt: H9KVD2

SCN5A ENST00000423572.7

TSL:1MANE Select

HGVSc / HGVSpc.2066G>Cp.Arg689Pro

Exon rankExon 14 of 28

missense

Prot: ENSP00000398266.2UniProt: Q14524-2

SCN5A ENST00000333535.9

TSL:1

HGVSc / HGVSpc.2066G>Cp.Arg689Pro

Exon rankExon 14 of 28

missense

Prot: ENSP00000328968.4UniProt: Q14524-1

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome Warning	AF: 6.84e-7	AC:1	Hom:0	AN:1461432	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 3 sources

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Cardiac arrhythmia (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	14
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Benign	18
CardioboostArm	Benign	0.00012
CardioboostCm	Benign	0.0019
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.74	D
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.23	N
FuncVEP CTI	Pathogenic	0.69
GPN-Star LLR	N/A	-6.2
GPN-Star score	N/A	6.2
LIST_S2	Benign	0.73	T
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	0.43	D
Mutation Taster	N/A	42/58	disease causing
MutationAssessor	Uncertain	2.4	M
PhyloP100	Benign	0.18
popEVE	Benign	-3.1
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.017	D
Varity_R	N/A	0.54
VESM-3B	Benign	-8.2

Showing 30 of 30 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.060
SpliceAI score (max)	Benign	0.030	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs199473145;

hg19: chr3-38639416;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar