3-38606071-G-T

Position:

• chr3-38606071-G-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000335.5(SCN5A):​c.1218C>A​(p.Asn406Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N406S) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN5A NM_000335.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 1.24

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a transmembrane_region Helical; Name=S6 of repeat I (size 20) in uniprot entity SCN5A_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_000335.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-38606072-T-C is described in Lovd as [Pathogenic].
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SCN5A. . Gene score misZ 2.7504 (greater than the threshold 3.09). Trascript score misZ 4.8279 (greater than threshold 3.09). GenCC has associacion of gene with 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, 0.994
• PP5: Variant 3-38606071-G-T is Pathogenic according to our data. Variant chr3-38606071-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 67648.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38606071-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.1218C>A	p.Asn406Lys	missense_variant	10/28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.1218C>A	p.Asn406Lys	missense_variant	10/28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.1218C>A	p.Asn406Lys	missense_variant	10/28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.1218C>A	p.Asn406Lys	missense_variant	10/28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

SCN5A-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

-

This variant has been previously reported in individuals with long QT syndrome and cardiac arrhythmias, including several in whom the variant was reported to be de novo (PMID: 15840476, 24112685, 29983085, 25254341, 32161207). Functional studies have demonstrated that the c.1218C>A (p.Asn406Lys) variant alters sodium channel function (PMID: 24112685, 29983085). The c.1218C>A (p.Asn406Lys) variant is absent from the gnomAD population database and thus is presumed to be rare. It affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.1218C>A (p.Asn406Lys) variant is classified as Pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 06, 2018

The N406K likely pathogenic variant in the SCN5A gene has been reported previously in association with LQTS (Tester et al., 2005; Kato et al., 2014). N406K was reported as apparently de novo in a male with a QTc interval of 638 ms at 1 day old and 478 ms at 8 months old (Kato et al., 2014). The N406K variant is not observed in large population cohorts (Lek et al., 2016). The N406K variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Furthermore, functional studies in Chinese hamster ovary cells demonstrated N406 alters the function of this sodium channel (Kato et al., 2014). Nevertheless, the N406K variant lacks observation in a significant number of affected individuals and segregation data, which would further clarify its pathogenicity. -

Long QT syndrome 3 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

May 06, 2021

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are both known mechanisms of disease in this gene. Loss of function is usually associated with Brugada syndrome 1 (MIM#601144) and sick sinus syndrome (SSS) (MIM#608567), whereas gain of function is usually associated with long QT syndrome (LQTS) (MIM#603830). Dilated cardiomyopathy 1E (DCM) (MIM#601154) can be caused by variants with either a loss- or gain of function mechanism (PMID: 29798782). However, some variants simultaneously result in both a loss- and gain of function effect, and have been observed in patients with LQTS, Brugada syndrome or SSS, and patients with a blended phenotype. Additionally, different studies have shown conflicting mechanisms in association with atrial fibrillation (MIM#614022) (PMID: 29806494, PMID: 19167345, PMID: 26798387). (I) 0108 - This gene is associated with both recessive and dominant disease. Most conditions associated with this gene are dominantly inherited, however sick sinus syndrome 1 (MIM#608567) can be caused by recessive variants (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from asparagine to lysine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in S6 of ion transport domain I (PMID: 24112685). (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. A different variant in the same codon resulting in a change to a serine has also been reported in an individual with Brugada syndrome (ClinVar, PMID: 15877619). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been previously reported in individuals with long QT syndrome (LQTS) including two de novo patients (ClinVar, PMID: 24112685, PMID: 15840476, PMID: 29766883, PMID: 25254341). Additionally, another variant with a different nucleotide change (C>G) resulting in the same amino acid change to lysine has also been reported in individuals with LQTS (ClinVar, PMID: 25904541). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies show that this variant alters the function of the sodium channel (PMID: 24112685, PMID: 15877619). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Congenital long QT syndrome Other:1

not provided, no classification provided

literature only

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

-

This variant has been reported as associated with Long QT syndrome in the following publications (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	Pathogenic	1.0
CardioboostCm	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	.;.;.;.;.;D;.;.;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	.;D;D;D;D;D;D;.;D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.4	.;H;.;.;.;H;.;.;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.9	D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;.;D;.;D;D;.;.
Vest4		1.0
MutPred		0.97		Gain of methylation at N406 (P = 0.0125);Gain of methylation at N406 (P = 0.0125);Gain of methylation at N406 (P = 0.0125);Gain of methylation at N406 (P = 0.0125);Gain of methylation at N406 (P = 0.0125);Gain of methylation at N406 (P = 0.0125);Gain of methylation at N406 (P = 0.0125);Gain of methylation at N406 (P = 0.0125);Gain of methylation at N406 (P = 0.0125);
MVP		0.97
MPC		1.2
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.94
gMVP		1.0

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: rs199473108; hg19: chr3-38647562;