NM_001099404.2:c.1066G>A
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2PP2PP3_StrongPP5_Very_Strong
The NM_001099404.2(SCN5A):c.1066G>A(p.Asp356Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. D356D) has been classified as Benign.
Frequency
Consequence
NM_001099404.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 15 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SCN5A | NM_001099404.2 | c.1066G>A | p.Asp356Asn | missense_variant | Exon 9 of 28 | ENST00000413689.6 | NP_001092874.1 | |
SCN5A | NM_000335.5 | c.1066G>A | p.Asp356Asn | missense_variant | Exon 9 of 28 | ENST00000423572.7 | NP_000326.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.1066G>A | p.Asp356Asn | missense_variant | Exon 9 of 28 | 5 | NM_001099404.2 | ENSP00000410257.1 | ||
SCN5A | ENST00000423572.7 | c.1066G>A | p.Asp356Asn | missense_variant | Exon 9 of 28 | 1 | NM_000335.5 | ENSP00000398266.2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152260Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000402 AC: 1AN: 249040Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135134
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461564Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 727060
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152260Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74386
ClinVar
Submissions by phenotype
not provided Pathogenic:2
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 356 of the SCN5A protein (p.Asp356Asn). 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 missense change has been observed in individuals with autosomal dominant Brugada syndrome, as well as several individuals referred for Brugada syndrome testing (PMID: 16325048, 20129283, 26173111, 29574140, 30193851, 31737537, 32931854, 33131149). ClinVar contains an entry for this variant (Variation ID: 67632). 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 disruptive. Experimental studies have shown that this missense change affects SCN5A function (PMID: 16325048, 21840964). For these reasons, this variant has been classified as Pathogenic. -
Reported multiple times in association with Brugada syndrome in published literature (PMID: 16325048, 19606473, 20129283, 22090166, 24136861, 26173111, 29574140, 30193851, 34461752, 28600387, 32893267, 39940965); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25863800, 18616619, 19606473, 29574140, 24903439, 22090165, 19027780, 18436145, 26154754, 22885917, 17504259, 21840964, 25904541, 16325048, 26173111, 30662450, 24136861, 30193851, 31737537, 33131149, 30868116, 34461752, 30203441, 37227351, 36516610, 38030334, 35305865, 39940965, 36578016, 32893267, 32931854, 34649698, 28600387, 20129283, 22090166, 35650162) -
Brugada syndrome Pathogenic:1Other:1
This variant has been reported as associated with Brugada syndrome in the following publications (PMID:16325048;PMID:20129283). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -
This missense variant replaces aspartic acid with asparagine at codon 356 in the pore-forming region of the transmembrane domain DI of the SCN5A protein. Functional studies have shown that this variant causes the loss of sodium channel activity (PMID: 16325048, 21840964). This variant has been reported in at least over 10 individuals affected with Brugada syndrome (PMID: 16325048, 24136861, 26173111, 29325976, 32893267, 34649698, 36516610), 8 unrelated individuals suspected of having Brugada syndrome (PMID: 20129283), 1 individual affected with sick sinus syndrome (PMID: 35650162), 2 individuals with other SCN5A-related cardiac symptoms (PMID: 22885917), and one individual affected with drug-resistant epilepsy (PMID: 30868116). This variant has been identified in 1/249040 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Brugada syndrome 1 Pathogenic:1
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Brugada syndrome (shorter-than-normal QT interval) Pathogenic:1
Variant summary: The SCN5A c.1066G>A (p.Asp356Asn) variant involves the alteration of a conserved nucleotide, is predicted to be damaging by 4/5 in silico tools and is located in Ion transport domain/S5-S6 extracellular loop that constitutes the pore region ((InterPro, Kapplinger_2010, Shinlapawittayatorn_2011). This variant is absent in 123598 control chromosomes from ExAC. This variant has been reported in at least 10 individuals with clinical features of Brugada syndrome and Brugada syndrome plus cardiac conduction defect (Makiyama_2005, Kapplinger_2010, Kanter_2012, Chockalingam_2012, Selga_2015). This variant was found to be one of four recurrent mutations in an international compendium of mutations in the SCN5A in patients referred for Brugada syndrome genetic testing (Kapplinger_2010). In vitro functional assays in HEK293 cells show that this variant leads to defective sodium current (Makiyama_2005, Shinlapawittayatorn_2011). One clinical diagnostic laboratory has classified this variant as likely pathogenic. Missense variants around this region such as p.D349N, p.G351D, p.G351V, p.T353I, p.Y352C, p.R367C, p.R367H, p.R367L, etc. have been reported in patients with BrS and other cardiac diseases, highlighting the functional importance of this region/domian. Taken together, this variant is classified as Pathogenic. -
Cardiovascular phenotype Pathogenic:1
The p.D356N variant (also known as c.1066G>A), located in coding exon 8 of the SCN5A gene, results from a G to A substitution at nucleotide position 1066. The aspartic acid at codon 356 is replaced by asparagine, an amino acid with highly similar properties. This variant was reported in individual(s) with features consistent with Brugada syndrome (Makiyama T, J. Am. Coll. Cardiol. 2005 Dec; 46(11):2100-6; Kapplinger JD, Heart Rhythm 2010 Jan; 7(1):33-46; Kanter RJ, Circulation 2012 Jan; 125(1):14-22; Mellor G et al. Circ Cardiovasc Genet, 2017 Jun;10; Renard E et al. JACC Clin Electrophysiol. 2023 Aug;9(8 Pt 1):1248-1261). In an assay testing SCN5A function, this variant showed a functionally abnormal result (Makiyama T, J. Am. Coll. Cardiol. 2005 Dec; 46(11):2100-6; Shinlapawittayatorn K, Circ Cardiovasc Genet 2011 Oct; 4(5):500-9; O'Neill MJ et al. Genet Med. 2022 Jun;24(6):1238-1248). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at