rs199473187

chr3-38580953-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001099404.2(SCN5A):c.3206C>T(p.Thr1069Met) variant causes a missense change. The variant allele was found at a frequency of 0.000043 in 1,606,186 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. T1069R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000044 (0 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:3 O:1
• Conservation: PhyloP100: 6.78

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SCN5A

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2	c.3206C>T	p.Thr1069Met	missense_variant	17/28	ENST00000413689.6
SCN5A	NM_000335.5	c.3206C>T	p.Thr1069Met	missense_variant	17/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.3206C>T	p.Thr1069Met	missense_variant	17/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.3206C>T	p.Thr1069Met	missense_variant	17/28	1	NM_000335.5	A1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152186 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000150 AC: 37 AN: 246942 Hom.: 0 AF XY: 0.000157 AC XY: 21 AN XY: 133878

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000931

Gnomad ASJ exome AF: 0.000203

Gnomad EAS exome AF: 0.0000557

Gnomad SAS exome AF: 0.0000662

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000440 AC: 64 AN: 1453882 Hom.: 0 Cov.: 30 AF XY: 0.0000471 AC XY: 34 AN XY: 721504

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.000854

Gnomad4 ASJ exome AF: 0.0000772

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0000349

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000145

Gnomad4 OTH exome AF: 0.0000333

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152304 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74464

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000888 Hom.: 0

Bravo AF: 0.0000567

ExAC AF: 0.000116 AC: 14

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Apr 21, 2014	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Thr1069Met (T1069M; c.3206C>T) in exon 17 of the SCN5A gene (NM_198056.2) We do not believe there is enough evidence to call this variant “disease-causing” at this time. It may instead be a rare benign variant that is more common in individuals with Hispanic ancestry. It has only been published in one “case” of LQTS, and this individual was also Hispanic. Furthermore, there is no phenotype data available for that patient, and so we cannot confirm that the individual actually had LQTS. This variant has previously been reported in just one Hispanic individual (the ethnicity is important) who had genetic testing for LQTS through the Familion laboratory (Tester et al. 2005; Kapplinger et al. 2009, Kapa et al. 2009). There is no phenotype information available for this individual, and we cannot assume that they have a confirmed clinical diagnosis of LQTS. Of note, genetic testing for the 2500 Familion cases reported by Kapplinger et al (2009) have an unusually low yield of 36% (vs. 70% in cohorts with a firm diagnoses of long QT syndrome), which suggests that not all of these patients have a firm diagnosis. Also, these papers have a lack of clarity regarding which variants were seen with another pathogenic variant (9% of the cohort had multiple variants). This is a non-conservative amino acid change, resulting in the replacement of a polar Threonine with a nonpolar Methionine in interdomain linker II-III. The Threonine at this location is NOT conserved across vertebrate species, and in fact the default amino acid is a Methionine in alligators and in 2 species of bird. Variation at nearby residues (+/- 10 amino acids) has NOT been associated with LQTS except for at residue Ser1079, which may argue against the functional importance of this region of the protein: (HGMD professional version as of January 17, 2014; and GeneDx report). This site in the protein is also not conserved across paralogue proteins: http://cardiodb.org/Paralogue_Annotation/residue.php?gene=SCN5A&position=1069. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “Probably Damaging” with a score of 0.993. In total the variant has been seen in 15 published controls or individuals from publicly available population datasets. The p.Thr1069Met variant is overrepresented among “Latino” individuals in the ExAC dataset, which currently includes variant calls on ~60,000 individuals of multiple ethnic backgrounds (Latino, European (non-Finnish), Finnish, South Asian, African & East Asian). It is present in 11 out of 5,749 Latinos in that database, which is an allele frequency of 0.1%. This estimates that ~2 out of every 1000 Latinos would carry the variant, which is a higher incidence than the overall estimated incidence of LQTS (1 in 2500 people). This variant is otherwise present in only 1 South Asian individual (out of 6,634) and 2 Caucasian individuals (out of 35,669). These individuals took part in a range of disease-specific and population genetic studies, and the curators made an effort to exclude individuals with severe pediatric diseases. There is only one individual with this variant listed in 1000 Genomes (http://browser.1000genomes.org/index.htm) as of 3/26/2015, and this individual also has Mexican ancestry. The variant was not observed in published controls, including 1300 from Kapplinger et al. 2009 (143 of them Hispanic). There is also no variation at this residue listed in the NHLBI Exome Sequencing Project dataset (http://evs.gs.washington.edu/EVS/), which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals who are NOT ethnicity-matched to our patient (who ha -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 16, 2024	Variant summary: SCN5A c.3206C>T (p.Thr1069Met) results in a non-conservative amino acid change located in the Sodium ion transport-associated domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 246942 control chromosomes, predominantly at a frequency of 0.00093 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 9 fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN5A causing Arrhythmia phenotype (0.0001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.3206C>T has been reported in the literature in individuals affected with Arrhythmia. These report(s) do not provide unequivocal conclusions about association of the variant with Arrhythmia.To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 31737537). ClinVar contains an entry for this variant (Variation ID: 67782). Based on the evidence outlined above, the variant was classified as likely benign. -

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 24, 2019	Reported in individuals with LQTS or referred for LQTS genetic testing and in one infant with sudden unexplained death who also harbored additional variants in four other cardiac genes (Tester et al., 2005; Kapa et al., 2009; Kapplinger et al., 2009; Goldenberg et al., 2011; Kapplinger et al., 2015; Methner et al., 2016); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 67782; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 19716085, 27435932, 31737537, 15840476, 16731473, 19841300, 21185501, 25904541, 28150151, 22581653, 28988457) -

Brugada syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Cardiac arrhythmia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Feb 09, 2023

This missense variant replaces threonine with methionine at codon 1069 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals suspected of having long QT syndrome (PMID: 25904541). This variant has been identified in 37/246942 chromosomes (32/34364 Latino chromosomes) in the general population by the Genome Aggregation Database (gnomAD). The relatively high frequency of this variant in the general population suggests that this variant is unlikely to be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 21, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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;PMID:19716085;PMID:19841300). 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	0.082
CardioboostArm	Benign	0.00038
CardioboostCm	Benign	0.00054
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Uncertain	0.040
Cadd	Benign	21
Dann	Uncertain	1.0
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Uncertain	0.67	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.057	T
MutationTaster	Benign	0.98	N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.7	D;D;D;D;N;D;D;N;N
REVEL	Uncertain	0.59
Sift	Uncertain	0.017	D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.061	T;D;T;T;T;T;D;T;T
Polyphen		1.0	D;D;.;D;.;D;D;.;.
Vest4		0.78
MutPred		0.78		Loss of glycosylation at T1069 (P = 0.0238);Loss of glycosylation at T1069 (P = 0.0238);Loss of glycosylation at T1069 (P = 0.0238);Loss of glycosylation at T1069 (P = 0.0238);Loss of glycosylation at T1069 (P = 0.0238);Loss of glycosylation at T1069 (P = 0.0238);Loss of glycosylation at T1069 (P = 0.0238);Loss of glycosylation at T1069 (P = 0.0238);Loss of glycosylation at T1069 (P = 0.0238);
MVP		0.77
MPC		0.17
ClinPred		0.30	T
GERP RS		5.1
Varity_R		0.071
gMVP		0.61

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: rs199473187; hg19: chr3-38622444; COSMIC: COSV61122207;