3-38587545-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP2 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

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 Pathogenic. Variant got 12 ACMG points.

• PM1: In a transmembrane_region Helical; Name=S2 of repeat II (size 19) in uniprot entity SCN5A_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_001099404.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-38587545-A-C is described in Lovd as [Pathogenic].
• PP2: Missense variant where missense usually causes diseases, SCN5A
• 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 id is 201472.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2	c.2291T>C	p.Met764Thr	missense_variant	15/28	ENST00000413689.6
SCN5A	NM_000335.5	c.2291T>C	p.Met764Thr	missense_variant	15/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.2291T>C	p.Met764Thr	missense_variant	15/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.2291T>C	p.Met764Thr	missense_variant	15/28	1	NM_000335.5	A1

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

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 16, 2012

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

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Apr 17, 2023

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
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.97	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
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
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
Polyphen		0.072	B;P;.;B;.;B;B;.;.
Vest4		0.93
MutPred		0.73		Gain of catalytic residue at M764 (P = 0.025);Gain of catalytic residue at M764 (P = 0.025);Gain of catalytic residue at M764 (P = 0.025);Gain of catalytic residue at M764 (P = 0.025);Gain of catalytic residue at M764 (P = 0.025);Gain of catalytic residue at M764 (P = 0.025);Gain of catalytic residue at M764 (P = 0.025);Gain of catalytic residue at M764 (P = 0.025);Gain of catalytic residue at M764 (P = 0.025);
MVP		0.90
MPC		0.54
ClinPred		1.0	D
GERP RS		4.1
Varity_R		0.93
gMVP		0.99

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: rs199473156; hg19: chr3-38629036;