3-38581170-C-T

Variant names:

• chr3-38581170-C-T
• rs137854609
• NM_001099404.2:c.2989G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 6P and 4B. PS3 PM5 BP4_Strong

The NM_000335.5(SCN5A):​c.2989G>A​(p.Ala997Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000739 in 1,611,142 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/24 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV005620739: Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID:24613995)". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A997S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000066 (0 hom.)
• Consequence: SCN5A NM_000335.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:17 B:1 O:1
• Conservation: PhyloP100: -3.52
• Publications: 25 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: Uncertain_significance. The variant received 2 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV005620739: Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 24613995)
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-38581170-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 9388.
• BP4: Computational evidence support a benign effect (MetaRNN=0.05895406).

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.2989G>A	p.Ala997Thr	missense	Exon 17 of 28	NP_001092874.1	H9KVD2
	SCN5A	NM_000335.5	MANE Select	c.2989G>A	p.Ala997Thr	missense	Exon 17 of 28	NP_000326.2
	SCN5A	NM_198056.3		c.2989G>A	p.Ala997Thr	missense	Exon 17 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.2989G>A	p.Ala997Thr	missense	Exon 17 of 28	ENSP00000410257.1	H9KVD2
	SCN5A	ENST00000423572.7	TSL:1 MANE Select	c.2989G>A	p.Ala997Thr	missense	Exon 17 of 28	ENSP00000398266.2	Q14524-2
	SCN5A	ENST00000333535.9	TSL:1	c.2989G>A	p.Ala997Thr	missense	Exon 17 of 28	ENSP00000328968.4	Q14524-1

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152018 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.000250

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000792 AC: 19 AN: 239824 AF XY: 0.000107

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000590

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000149

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000665 AC: 97 AN: 1459124 Hom.: 0 Cov.: 36 AF XY: 0.0000730 AC XY: 53 AN XY: 725724

African (AFR) AF: 0.0000299 AC: 1 AN: 33466

American (AMR) AF: 0.0000675 AC: 3 AN: 44416

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26048

East Asian (EAS) AF: 0.00 AC: 0 AN: 39636

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85970

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52838

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.0000783 AC: 87 AN: 1110772

Other (OTH) AF: 0.0000830 AC: 5 AN: 60220

GnomAD4 genome AF: 0.000145 AC: 22 AN: 152018 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74260

African (AFR) AF: 0.0000242 AC: 1 AN: 41392

American (AMR) AF: 0.000262 AC: 4 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

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

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 67992

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000565 Hom.: 0

Bravo AF: 0.0000869

ExAC AF: 0.000108 AC: 13

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	5	-	not provided (6)
-	2	-	Cardiac arrhythmia (2)
-	2	-	Sick sinus syndrome 1 (2)
-	1	-	Brugada syndrome (2)
-	1	-	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Dilated cardiomyopathy 1E (1)
-	1	-	Long QT syndrome 3 (1)
-	1	-	Progressive familial heart block, type 1A (1)
-	1	-	SUDDEN INFANT DEATH SYNDROME;C1142166:Brugada syndrome (1)
-	1	-	SUDDEN INFANT DEATH SYNDROME;C1832680:Dilated cardiomyopathy 1E;C1837845:Sick sinus syndrome 1;C1859062:Long QT syndrome 3;C1879286:Progressive familial heart block, type 1A;C2751898:Ventricular fibrillation, paroxysmal familial, type 1;C3151464:Atrial fibrillation, familial, 10;C4551804:Brugada syndrome 1 (1)
-	1	-	Ventricular fibrillation, paroxysmal familial, type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
CardioboostArm	Benign	0.0000015
CardioboostCm	Benign	0.0023
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	0.017
DANN	Benign	0.67
DEOGEN2	Benign	0.38	T
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.72	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.059	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	-0.080	N
PhyloP100		-3.5
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.57	N
REVEL	Uncertain	0.48
Sift	Benign	0.53	T
Sift4G	Benign	0.68	T
Polyphen		0.0010	B
Vest4		0.095
MVP		0.98
MPC		0.029
ClinPred		0.018	T
GERP RS		-11
Varity_R		0.022
gMVP		0.46
Mutation Taster		=0/100	disease causing

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: rs137854609; hg19: chr3-38622661;