rs199473587

chr3-38585845-C-T

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.2633G>A(p.Arg878His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,880 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. R878C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1 O:1
• Conservation: PhyloP100: 7.91

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 repeat II (size 270) in uniprot entity SCN5A_HUMAN there are 72 pathogenic changes around while only 4 benign (95%) 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 chr3-38585846-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 67744.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, SCN5A
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant 3-38585845-C-T is Pathogenic according to our data. Variant chr3-38585845-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 67745.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, not_provided=1, Pathogenic=1, Uncertain_significance=1}. Variant chr3-38585845-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2	c.2633G>A	p.Arg878His	missense_variant	16/28	ENST00000413689.6
SCN5A	NM_000335.5	c.2633G>A	p.Arg878His	missense_variant	16/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.2633G>A	p.Arg878His	missense_variant	16/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.2633G>A	p.Arg878His	missense_variant	16/28	1	NM_000335.5	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461880 Hom.: 0 Cov.: 36 AF XY: 0.00000138 AC XY: 1 AN XY: 727236

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.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2022	Published functional studies demonstrate significantly reduced peak current, suggesting a dominant negative effect (Kapplinger et al., 2015; O'Neill et al., 2022); 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: 23308164, 30193851, 30662450, 25904541, 20129283, 35305865, 24136861, 33712547, 29728395, 32268277, 33641026) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 03, 2023	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 878 of the SCN5A protein (p.Arg878His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of SCN5A-related conditions (PMID: 20129283, 30193851; Invitae). ClinVar contains an entry for this variant (Variation ID: 67745). 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: 25904541). This variant disrupts the p.Arg878 amino acid residue in SCN5A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18616619, 20960618, 26036855, 28341781, 28781330). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Brugada syndrome Pathogenic:1 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 08, 2023	This missense variant replaces arginine with histidine at codon 878 of the transmembrane domain DII 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). A functional study has shown that this variant causes complete loss of peak current in transfected cells (PMID: 25904541). This variant has been reported in at least six unrelated individuals affected with Brugada syndrome or with other clinical features of SCN5A-related conditions (PMID: 20129283, 30193851, 32268277, 32893267, ClinVar SCV001505358.2). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Arg878Cys, is known to be pathogenic (Clinvar variation ID 67744), indicating that arginine at this position is important for SCN5A protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. -
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 Brugada syndrome in the following publications (PMID:20129283). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 29, 2021

The c.2633G>A (p.R878H) alteration is located in exon 16 (coding exon 15) of the SCN5A gene. This alteration results from a G to A substitution at nucleotide position 2633, causing the arginine (R) at amino acid position 878 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
CardioboostArm	Pathogenic	1.0
CardioboostCm	Uncertain	0.76
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.98	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	0.86	D
PROVEAN	Pathogenic	-4.8	D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.039	D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;.;D;.;D;D;.;.
Vest4		0.97
MutPred		0.87		Gain of glycosylation at S873 (P = 0.0723);Gain of glycosylation at S873 (P = 0.0723);Gain of glycosylation at S873 (P = 0.0723);Gain of glycosylation at S873 (P = 0.0723);Gain of glycosylation at S873 (P = 0.0723);Gain of glycosylation at S873 (P = 0.0723);Gain of glycosylation at S873 (P = 0.0723);Gain of glycosylation at S873 (P = 0.0723);Gain of glycosylation at S873 (P = 0.0723);
MVP		0.99
MPC		1.2
ClinPred		1.0	D
GERP RS		4.2
Varity_R		0.87
gMVP		0.95

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: rs199473587; hg19: chr3-38627336;