chr3-38551513-G-A

Variant names:

• chr3-38551513-G-A
• rs199473282
• NM_001099404.2:c.4859C>T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_000335.5(SCN5A):​c.4856C>T​(p.Thr1619Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,613,728 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T1619T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: SCN5A NM_000335.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 O:2
• Conservation: PhyloP100: 8.13

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]

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PM1: In a repeat IV (size 297) in uniprot entity SCN5A_HUMAN there are 68 pathogenic changes around while only 2 benign (97%) in NM_000335.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the SCN5A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 99 curated pathogenic missense variants (we use a threshold of 10). The gene has 60 curated benign missense variants. Gene score misZ: 2.7504 (below the threshold of 3.09). Trascript score misZ: 4.8279 (above the threshold of 3.09). GenCC associations: The gene is linked to progressive familial heart block, type 1A, Brugada syndrome, familial sick sinus syndrome, short QT syndrome, paroxysmal familial ventricular fibrillation, progressive familial heart block, long QT syndrome 3, familial atrial fibrillation, catecholaminergic polymorphic ventricular tachycardia, dilated cardiomyopathy, dilated cardiomyopathy 1E, arrhythmogenic right ventricular cardiomyopathy, Brugada syndrome 1, atrial standstill, familial isolated dilated cardiomyopathy, familial long QT syndrome, sick sinus syndrome 1.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 3-38551513-G-A is Pathogenic according to our data. Variant chr3-38551513-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 67932.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38551513-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.4859C>T	p.Thr1620Met	missense_variant	Exon 28 of 28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.4856C>T	p.Thr1619Met	missense_variant	Exon 28 of 28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.4859C>T	p.Thr1620Met	missense_variant	Exon 28 of 28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.4856C>T	p.Thr1619Met	missense_variant	Exon 28 of 28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152020 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250918 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135682

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1461708 Hom.: 0 Cov.: 35 AF XY: 0.0000110 AC XY: 8 AN XY: 727136

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152020 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74246

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Aug 05, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Multiple studies have examined the functional effect of the p.(T1620M) variant, with the general conclusion that this variant impacts sodium ion channel function (PMID: 11827685, 30662450, 10532948, 10618304); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 11786529, 10618304, 11013131, 23785128, 29728395, 30662450, 30847666, 20129283, 10532948, 11029409, 11123251, 9521325, 34135346, 33131149, 11827685, 15520322, 30203441, 34076677) -

Jan 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1620 of the SCN5A protein (p.Thr1620Met). This variant is present in population databases (rs199473282, gnomAD 0.0009%). This missense change has been observed in individual(s) with Brugada syndrome and/or clinical features of SCN5A-related conditions (PMID: 9521325, 15520322, 20129283, 23785128, 29728395, 30847666, 34076677). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 67932). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects SCN5A function (PMID: 9521325, 10532948, 10618304, 11029409, 11123251, 11827685). For these reasons, this variant has been classified as Pathogenic. -

Brugada syndrome 1 Pathogenic:1 Other:1

Jun 15, 2022

Institute of Human Genetics, Heidelberg University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

reported as secondary finding -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Brugada syndrome Pathogenic:1 Other:1

-

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:9521325;PMID:20129283;PMID:10618304;PMID:15520322;PMID:11013131). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

Jun 09, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces threonine with methionine at codon 1620 of the SCN5A protein. This variant is found within the highly conserved transmembrane domain DIV (a.a.1530-1771). Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with Brugada syndrome(PMID: 32893267). Functional studies have generally shown that this variant alters the sodium channel function (PMID: 9521325, 10532948, 10618304, 11029409, 11123251, 11827685, 30050137). This variant has been reported in multiple unrelated individuals affected with Brugada syndrome (PMID: 15520322, 20129283, 25904541), as well as in an individual affected with fever-induced Brugada syndrome (PMID: 36516610). It has been shown that this segregates with disease in six relatives from a family (PMID: 9521325, 10662748, 15520322). This variant has been identified in 1/250918 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

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 Pathogenic:1

Jul 01, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiac arrhythmia Pathogenic:1

Apr 15, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces threonine with methionine at codon 1620 of the SCN5A protein. This variant is found within the highly conserved transmembrane domain DIV (a.a.1530-1771). Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with Brugada syndrome(PMID: 32893267). Functional studies have generally shown that this variant alters the sodium channel function (PMID: 9521325, 10532948, 10618304, 11029409, 11123251, 11827685, 30050137). This variant has been reported in multiple unrelated individuals affected with Brugada syndrome (PMID: 15520322, 20129283, 25904541), as well as in an individual affected with fever-induced Brugada syndrome (PMID: 36516610). It has been shown that this segregates with disease in six relatives from a family (PMID: 9521325, 10662748, 15520322). This variant has been identified in 1/250918 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
CardioboostCm	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	.;.;.;.;.;D;.;.;.
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	.;D;D;D;D;D;D;.;D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	.;.;.;.;.;H;.;.;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.3	D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D
Polyphen		0.98	D;D;.;D;.;D;P;.;.
Vest4		0.88
MutPred		0.94		.;.;Gain of MoRF binding (P = 0.0977);.;.;Gain of MoRF binding (P = 0.0977);.;.;.;
MVP		0.99
MPC		1.3
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.85
gMVP		0.95

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

Publications

LitVar

Other links and lift over

dbSNP: rs199473282; hg19: chr3-38593004; COSMIC: COSV104413440; COSMIC: COSV104413440;