rs199473126

chr3-38603890-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Strong

The NM_001099404.2(SCN5A):c.1712G>T(p.Ser571Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000266 in 1,613,874 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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5 O:2
• Conservation: PhyloP100: 7.91

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SCN5A
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2	c.1712G>T	p.Ser571Ile	missense_variant	12/28	ENST00000413689.6
SCN5A	NM_000335.5	c.1712G>T	p.Ser571Ile	missense_variant	12/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.1712G>T	p.Ser571Ile	missense_variant	12/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.1712G>T	p.Ser571Ile	missense_variant	12/28	1	NM_000335.5	A1

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152228 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000864

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: 0.0000321 AC: 8 AN: 249010 Hom.: 0 AF XY: 0.0000222 AC XY: 3 AN XY: 135084

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.0000355

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000260 AC: 38 AN: 1461646 Hom.: 0 Cov.: 31 AF XY: 0.0000248 AC XY: 18 AN XY: 727114

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000459

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.0000189

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152228 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74362

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000864

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

Alfa AF: 0.0000810 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cardiac arrhythmia Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 11, 2024	This missense variant replaces serine with isoleucine at codon 571 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). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in one individual referred for long QT syndrome genetic testing (PMID:19716085, 25904541). This variant has been identified in 10/280396 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 06, 2022	This missense variant replaces serine with isoleucine at codon 571 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). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in one individual referred for long QT syndrome genetic testing (PMID:19716085, 25904541). This variant has been identified in 10/280396 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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 29, 2023

This sequence change replaces serine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 571 of the SCN5A protein (p.Ser571Ile). This variant is present in population databases (rs199473126, gnomAD 0.02%). This missense change has been observed in individual(s) with long QT syndrome (PMID: 19716085, 25904541). ClinVar contains an entry for this variant (Variation ID: 67681). 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 tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Long QT syndrome Uncertain:1

Uncertain significance, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Aug 01, 2016

Found in patient having exome sequencing for an unrelated indication. No known history of Long QT syndrome. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 05, 2021

The c.1712G>T (p.S571I) alteration is located in exon 12 (coding exon 11) of the SCN5A gene. This alteration results from a G to T substitution at nucleotide position 1712, causing the serine (S) at amino acid position 571 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

SCN5A-related disorder Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

-

Variant interpreted as Uncertain significance and reported on 10-10-2018 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

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:19716085). 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	0.26
CardioboostArm	Benign	0.0055
CardioboostCm	Benign	0.0051
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.24
Cadd	Uncertain	23
Dann	Uncertain	1.0
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	0.97	D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-4.3	D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0020	D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.060	T;T;T;T;T;T;T;T;T
Polyphen		0.99	D;D;.;D;.;D;D;.;.
Vest4		0.92
MutPred		0.77		Loss of phosphorylation at S571 (P = 0.0157);Loss of phosphorylation at S571 (P = 0.0157);Loss of phosphorylation at S571 (P = 0.0157);Loss of phosphorylation at S571 (P = 0.0157);Loss of phosphorylation at S571 (P = 0.0157);Loss of phosphorylation at S571 (P = 0.0157);Loss of phosphorylation at S571 (P = 0.0157);Loss of phosphorylation at S571 (P = 0.0157);Loss of phosphorylation at S571 (P = 0.0157);
MVP		0.90
MPC		1.2
ClinPred		0.84	D
GERP RS		4.1
Varity_R		0.53
gMVP		0.82

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: rs199473126; hg19: chr3-38645381;