chr3-38585821-T-G

Variant names:

• chr3-38585821-T-G
• rs199473169
• NM_001099404.2:c.2657A>C

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_001099404.2(SCN5A):​c.2657A>C​(p.His886Pro) 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H886R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 O:1
• Conservation: PhyloP100: 8.02
• Publications: 5 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: ClinGen, Orphanet
• Brugada syndrome 1

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

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

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

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

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

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

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

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 18 uncertain in NM_001099404.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 3-38585821-T-G is Pathogenic according to our data. Variant chr3-38585821-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 67746. Variant chr3-38585821-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 67746. Variant chr3-38585821-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 67746. Variant chr3-38585821-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 67746. Variant chr3-38585821-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 67746. Variant chr3-38585821-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 67746. Variant chr3-38585821-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 67746. Variant chr3-38585821-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 67746. Variant chr3-38585821-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 67746. Variant chr3-38585821-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 67746. Variant chr3-38585821-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 67746. Variant chr3-38585821-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 67746. Variant chr3-38585821-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 67746. Variant chr3-38585821-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 67746. Variant chr3-38585821-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 67746. Variant chr3-38585821-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 67746.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.2657A>C	p.His886Pro	missense_variant	Exon 16 of 28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.2657A>C	p.His886Pro	missense_variant	Exon 16 of 28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.2657A>C	p.His886Pro	missense_variant	Exon 16 of 28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.2657A>C	p.His886Pro	missense_variant	Exon 16 of 28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Brugada syndrome Pathogenic:1 Other:1

Jun 16, 2017

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

This variant has been reported as associated with Brugada syndrome in the following publications (PMID:20129283). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

Cardiac arrhythmia Uncertain:1

Mar 28, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
CardioboostArm	Pathogenic	1.0
CardioboostCm	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	.;.;.;.;.;D;.;.;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	.;D;D;D;D;D;D;.;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	.;H;.;.;.;H;.;.;.
PhyloP100		8.0
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-9.3	D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0070	D;D;D;D;D;D;D;D;D
Polyphen		0.99	D;D;.;D;.;D;D;.;.
Vest4		0.98
MutPred		0.94		Gain of catalytic residue at H886 (P = 0.1238);Gain of catalytic residue at H886 (P = 0.1238);Gain of catalytic residue at H886 (P = 0.1238);Gain of catalytic residue at H886 (P = 0.1238);Gain of catalytic residue at H886 (P = 0.1238);Gain of catalytic residue at H886 (P = 0.1238);Gain of catalytic residue at H886 (P = 0.1238);Gain of catalytic residue at H886 (P = 0.1238);Gain of catalytic residue at H886 (P = 0.1238);
MVP		1.0
MPC		0.63
ClinPred		1.0	D
GERP RS		4.2
Varity_R		0.97
gMVP		1.0
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: rs199473169; hg19: chr3-38627312;