3-38555714-T-G

Variant names:

• chr3-38555714-T-G
• rs199473262
• NM_001099404.2:c.4484A>C

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PS3 PM1 PM2 PP3_Strong PP5

The NM_000335.5(SCN5A):​c.4481A>C​(p.Tyr1494Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 14/24 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000235488: mutation of the Tyrosine 1495 residue to Y1495F significantly altered phosphorylation and consequently sodium channel inactivation (Ahern et al., 2005).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y1494C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SCN5A NM_000335.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 O:1
• Conservation: PhyloP100: 7.97
• Publications: 9 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: Pathogenic. The variant received 13 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000235488: mutation of the Tyrosine 1495 residue to Y1495F significantly altered phosphorylation and consequently sodium channel inactivation (Ahern et al., 2005).
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 17 uncertain in NM_000335.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974
• PP5: Variant 3-38555714-T-G is Pathogenic according to our data. Variant chr3-38555714-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 67900.

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.4484A>C	p.Tyr1495Ser	missense	Exon 26 of 28	NP_001092874.1	H9KVD2
	SCN5A	NM_000335.5	MANE Select	c.4481A>C	p.Tyr1494Ser	missense	Exon 26 of 28	NP_000326.2
	SCN5A	NM_198056.3		c.4484A>C	p.Tyr1495Ser	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.4484A>C	p.Tyr1495Ser	missense	Exon 26 of 28	ENSP00000410257.1	H9KVD2
	SCN5A	ENST00000423572.7	TSL:1 MANE Select	c.4481A>C	p.Tyr1494Ser	missense	Exon 26 of 28	ENSP00000398266.2	Q14524-2
	SCN5A	ENST00000333535.9	TSL:1	c.4484A>C	p.Tyr1495Ser	missense	Exon 26 of 28	ENSP00000328968.4	Q14524-1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	-	not provided (2)
-	-	-	Congenital long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
CardioboostArm	Pathogenic	1.0
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	27
DANN	Benign	0.96
DEOGEN2	Pathogenic	0.88	D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		8.0
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-8.3	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.77	P
Vest4		0.97
MutPred		0.84		Gain of disorder (P = 0.0379)
MVP		0.99
MPC		1.3
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.97
gMVP		0.99
Mutation Taster		=0/100	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: rs199473262; hg19: chr3-38597205;