rs199473118

Positions:

• chr3-38604067-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_001099404.2(SCN5A):​c.1535C>T​(p.Thr512Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 1,450,940 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: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6 O:2
• Conservation: PhyloP100: 0.638

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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 4.7729 (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, 0.889

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.1535C>T	p.Thr512Ile	missense_variant	12/28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.1535C>T	p.Thr512Ile	missense_variant	12/28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.1535C>T	p.Thr512Ile	missense_variant	12/28	5	NM_001099404.2	ENSP00000410257	P4
SCN5A	ENST00000423572.7	c.1535C>T	p.Thr512Ile	missense_variant	12/28	1	NM_000335.5	ENSP00000398266	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000437 AC: 1 AN: 229040 Hom.: 0 AF XY: 0.00000806 AC XY: 1 AN XY: 124042

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: 0.00000969

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000131 AC: 19 AN: 1450940 Hom.: 0 Cov.: 32 AF XY: 0.0000125 AC XY: 9 AN XY: 720618

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000238

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000136

Gnomad4 OTH exome AF: 0.0000333

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000279 Hom.: 0

Bravo AF: 0.0000113

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 17, 2017	Variant summary: The SCN5A c.1535C>T (p.Thr512Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. 2/3 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 1/67122 control chromosomes at a frequency of 0.0000149, which does not exceed the estimated maximal expected allele frequency of a pathogenic SCN5A variant (0.0001). This variant was identified in at least one pt with cardiac conduction disease without strong segregation due to possibly reduced penetrance and in 2 patients with DCM/HCM. Functional study showed that the variant caused abnormal gating effects. GeneReviews cites this variant as pathogenic, although other clinical diagnostic laboratories classify the variant as VUS. Taking together, the variant is classified as VUS-Possibly Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 27, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Reported in patients with arrhythmia and cardiomyopathy and in an unaffected relative (Viswanathan et al., 2003; Priganc et al., 2016); This variant is associated with the following publications: (PMID: 12569159, 27554632, 29728395) -
Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Apr 22, 2016	The variant has been reported in one 2-year-old individual with second-degree atrioventricular (AV) block (Viswanathan 2003). Functional expression studies showed that voltage-dependent activation and inactivation had enhanced slow activation and slow recovery from inactivation when compared to wildtype (OMIM 600163.0031; Viswanathan 2003). -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 26, 2023	Experimental studies have shown that this missense change affects SCN5A function (PMID: 12569159). 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. 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. ClinVar contains an entry for this variant (Variation ID: 67665). This missense change has been observed in individual(s) with atrioventricular (AV) conduction block and cardiomyopathy (PMID: 12569159, 27554632). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 512 of the SCN5A protein (p.Thr512Ile). -

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 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 24, 2022

- -

Cardiac arrhythmia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Oct 02, 2023

This missense variant replaces threonine with isoleucine at codon 512 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. A functional study has suggested that this variant may affect sodium channel function (PMID: 12569159). This variant has been reported in an individual affected with atrioventricular block (PMID: 12569159), as well as in an individual affected with dilated cardiomyopathy and an individual affected with hypertrophic cardiomyopathy (PMID: 27554632). This variant has been identified in 1/229040 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. -

Brugada syndrome 1 Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Conduction system disorder 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 Cardiac conduction disease in the following publications (PMID:12569159). 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	0.15
CardioboostCm	Benign	0.0045
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	14
DANN	Benign	0.96
DEOGEN2	Uncertain	0.47	.;.;.;.;.;T;.;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.71	.;T;T;T;T;T;T;.;T
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	0.55	.;N;.;.;.;N;.;.;.
MutationTaster	Benign	3.1e-9	A;A;A;A;A;A;A;A;A;A
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.56	N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.54
Sift	Benign	0.14	T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.18	T;T;T;T;T;T;T;T;T
Polyphen		0.0	B;B;.;B;.;B;B;.;.
Vest4		0.64
MutPred		0.72		Loss of relative solvent accessibility (P = 0.0186);Loss of relative solvent accessibility (P = 0.0186);Loss of relative solvent accessibility (P = 0.0186);Loss of relative solvent accessibility (P = 0.0186);Loss of relative solvent accessibility (P = 0.0186);Loss of relative solvent accessibility (P = 0.0186);Loss of relative solvent accessibility (P = 0.0186);Loss of relative solvent accessibility (P = 0.0186);Loss of relative solvent accessibility (P = 0.0186);
MVP		0.96
MPC		0.38
ClinPred		0.060	T
GERP RS		0.47
Varity_R		0.047
gMVP		0.62

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: rs199473118; hg19: chr3-38645558;