3-38551373-C-T

Variant names:

• chr3-38551373-C-T
• rs199473293
• NM_001099404.2:c.4999G>A

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.4999G>A​(p.Val1667Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. V1667F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:2 O:1
• Conservation: PhyloP100: 6.14
• Publications: 12 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 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_001099404.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.959
• PP5: Variant 3-38551373-C-T is Pathogenic according to our data. Variant chr3-38551373-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 67949.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.4999G>A	p.Val1667Ile	missense_variant	Exon 28 of 28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.4996G>A	p.Val1666Ile	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.4999G>A	p.Val1667Ile	missense_variant	Exon 28 of 28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.4996G>A	p.Val1666Ile	missense_variant	Exon 28 of 28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251492 AF XY: 0.00000736

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461894 Hom.: 0 Cov.: 35 AF XY: 0.00000275 AC XY: 2 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Oct 28, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in association with LQTS and Brugada syndrome in published literature (PMID: 15996170, 20129283, 15090000, 11274952, 29709244, 15840476, 21911102); Not observed at significant frequency in large population cohorts (gnomAD); A published functional study suggests the p.(V1667I) variant is associated with epinephrine-induced QT prolongation (PMID: 32437023); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 15090000, 15121794, 15996170, 20129283, 20566482, 11274952, 33131149, 30291343, 30203441, 29709244, 19843921, 15840476, 21911102, 22936642, 2437023, 32437023) -

Feb 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1667 of the SCN5A protein (p.Val1667Ile). This variant is present in population databases (rs199473293, gnomAD 0.0009%). This missense change has been observed in individuals with long QT syndrome and Brugada syndrome (PMID: 2437023, 11274952, 19843921, 30291343, 32437023). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 67949). 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: 32437023). For these reasons, this variant has been classified as Pathogenic. -

Cardiac arrhythmia Pathogenic:1 Uncertain:1

Aug 15, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces valine with isoleucine at codon 1667 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). An in vitro functional study has shown that this variant causes an increased sodium channel density, depolarizing shift in the steady-state inactivation, and accelerated recovery from inactivation (PMID: 32437023). This variant has been reported in a few individuals affected with or suspected of having long QT syndrome (PMID:11274952, 15840476, 20129283, 27566755), in an individual affected with ventricular tachycardia (PMID: 15996170), in an individual affected with Brugada syndrome (PMID: 19843921), in three related individuals with epinephrine-induced marked QT prolongation (PMID: 32437023), and in several asymptomatic relatives from two families (PMID:11274952, 32437023). This variant has been identified in 1/251492 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Apr 27, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces valine with isoleucine at codon 1667 of the SCN5A protein. This variant is also known as p.Val1666Ile in the literature based on a different NM_000335 transcript. This variant is found within a highly conserved region of the transmembrane domain DIV. Rare nontruncating variants in transmembrane and linker regions have been shown to be significantly overrepresented in individuals with Long QT syndrome and Brugada syndrome (PMID: 32893267). An in vitro functional study has shown that this variant causes an increased sodium channel density, depolarizing shift in the steady-state inactivation, and accelerated recovery from inactivation (PMID: 32437023). This variant has been reported in a few individuals affected with or suspected of having long QT syndrome (PMID:11274952, 15840476, 20129283, 27566755), in an individual affected with ventricular tachycardia (PMID: 15996170), in an individual affected with Brugada syndrome (PMID: 19843921), in three related individuals with epinephrine-induced marked QT prolongation (PMID: 32437023), and in an individual affected with arrhythmia with family history of sudden cardiac death (communication with an external laboratory; ClinVar SCV000617273.1). It has been shown that this variant segregates with disease in three of the families (PMID: 11274952, 32437023, communication with an external laboratory; ClinVar SCV000617273.1). This variant has been identified in 1/251492 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Long QT syndrome Pathogenic:1

-

Medical Research Institute, Tokyo Medical and Dental University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Cardiovascular phenotype Pathogenic:1

Aug 15, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4999G>A (p.V1667I) alteration is located in exon 28 (coding exon 27) of the SCN5A gene. This alteration results from a G to A substitution at nucleotide position 4999, causing the valine (V) at amino acid position 1667 to be replaced by an isoleucine (I). Based on data from gnomAD, the A allele has an overall frequency of <0.001% (1/251492) total alleles studied. The highest observed frequency was 0.001% (1/113768) of European (non-Finnish) alleles. This variant has been reported in individuals with long QT syndrome (LQTS), including segregating with disease in two families (Piippo, 2001; Tester, 2005; Hekkala, 2010; M&auml;&auml;tt&auml;nen, 2011; M&auml;&auml;tt&auml;nen, 2013; Amin, 2018; Nakajima, 2020). This amino acid position is highly conserved in available vertebrate species. Additionally, in vitro analysis showed this variant may impact protein function (Nakajima, 2020). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

Congenital long QT syndrome 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 Long QT syndrome in the following publications (PMID:11274952;PMID:15840476). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
CardioboostArm	Pathogenic	1.0
CardioboostCm	Benign	0.095
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	.;.;.;.;.;D;.;.;.
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	.;D;D;D;D;D;D;.;D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.64	.;.;.;.;.;N;.;.;.
PhyloP100		6.1
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.96	N;N;N;N;N;N;N;N;N
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.35	T;T;T;T;T;T;T;T;T
Polyphen		1.0	D;D;.;D;.;D;D;.;.
Vest4		0.82
MutPred		0.89		.;.;Loss of catalytic residue at V1667 (P = 0.0488);.;.;Loss of catalytic residue at V1667 (P = 0.0488);.;.;.;
MVP		0.95
MPC		1.3
ClinPred		0.68	D
GERP RS		4.7
Varity_R		0.63
gMVP		0.93
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: rs199473293; hg19: chr3-38592864; COSMIC: COSV61140060; COSMIC: COSV61140060;