3-38587545-A-G

Variant names:

• chr3-38587545-A-G
• rs199473156
• NM_001099404.2:c.2291T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001099404.2(SCN5A):​c.2291T>C​(p.Met764Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,704 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. M764R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 9.28
• Publications: 7 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 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.955
• PP5: Variant 3-38587545-A-G is Pathogenic according to our data. Variant chr3-38587545-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 201472.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.2291T>C	p.Met764Thr	missense_variant	Exon 15 of 28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.2291T>C	p.Met764Thr	missense_variant	Exon 15 of 28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.2291T>C	p.Met764Thr	missense_variant	Exon 15 of 28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.2291T>C	p.Met764Thr	missense_variant	Exon 15 of 28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461704 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727136

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

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: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111864

Other (OTH) AF: 0.00 AC: 0 AN: 60374

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000427 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Nov 16, 2012

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Met764Thr (ATG>ACG): c.2291 T>C in exon 15 of the SCN5A gene (NM_198056.2) The Met764Thr mutation in the SCN5A gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. However, a mutation affecting this same codon, Met764Arg, has been reported in one individual with Brugada syndrome who also harbored another mutation in the SCN5A gene (Kapplinger J et al., 2010). Mutations in nearby residues (Gly758Glu, Ile759Phe, Asp772Asn) have been reported in association with arrhythmia, further supporting the functional importance of this codon and this region of the protein. Met764Thr, located in the DII-S2 region of the SCN5A gene, results in a non-conservative amino acid substitution of a non-polar Methionine residue with a polar Threonine residue. Furthermore, the NHLBI ESP Exome Variant Server reports Met764Thr was not observed in approximately 6,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations .In summary, Met764Thr in the SCN5A gene is interpreted as a likely disease-causing mutation. The variant is found in LQT panel(s).

Cardiac arrhythmia Uncertain:1

Apr 17, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces methionine with threonine at codon 764 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). This variant is found within a highly conserved region of the transmembrane domain DII. Rare nontruncating variants in this region have been shown to be significantly overrepresented in individuals with SCN5A-related disorders (PMID: 32893267). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in an individual affected with long QT syndrome (communication with an external laboratory; GeneDx SCV000235405.10). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different missense variants occurring at the same codon, p.Met764Lys, p.Met764Val, and p.Met764Arg, have been reported in individuals affected with Brugada syndrome, idiopathic ventricular fibrillation, and sudden unexplained infant death, indicating that methionine at this position is important for the protein function (PMID: 20129283, 29343803, 29907895, 30371189). Although there is a suspicion for a pathogenic role, 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.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
CardioboostArm	Pathogenic	1.0
CardioboostCm	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0	.;.;.;.;.;D;.;.;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.0	.;D;D;D;D;D;D;.;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.0	.;M;.;.;.;M;.;.;.
PhyloP100		9.3
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.9	D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0050	D;D;D;D;D;D;D;D;D
Vest4		0.93
ClinPred		1.0	D
GERP RS		4.1
Varity_R		0.93
gMVP		0.99
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs199473156; hg19: chr3-38629036;