3-38620894-G-C

Variant names:

• chr3-38620894-G-C
• rs199473558
• NM_001099404.2:c.560C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PS1 PM2 PP2

The NM_000335.5(SCN5A):​c.560C>G​(p.Thr187Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,460,124 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in Lovd.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: SCN5A NM_000335.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 10.0

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 Likely_pathogenic. Variant got 7 ACMG points.

• PS1: Transcript NM_000335.5 (SCN5A) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the SCN5A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 99 curated pathogenic missense variants (we use a threshold of 10). The gene has 60 curated benign missense variants. Gene score misZ: 2.7504 (below the threshold of 3.09). Trascript score misZ: 4.8279 (above the threshold of 3.09). GenCC associations: The gene is linked to 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.560C>G	p.Thr187Ser	missense_variant	Exon 5 of 28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.560C>G	p.Thr187Ser	missense_variant	Exon 5 of 28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.560C>G	p.Thr187Ser	missense_variant	Exon 5 of 28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.560C>G	p.Thr187Ser	missense_variant	Exon 5 of 28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000163 AC: 4 AN: 245776 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 133410

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000117

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1460124 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726162

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000112

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Dec 06, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 187 of the SCN5A protein (p.Thr187Ser). This variant is present in population databases (rs199473558, gnomAD 0.009%). This missense change has been observed in individual(s) with Brugada syndrome (PMID: 30193851; Invitae). ClinVar contains an entry for this variant (Variation ID: 532122). 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. This variant disrupts the p.Thr187 amino acid residue in SCN5A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16325048, 20539757, 25348405). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. -

Feb 09, 2021

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

May 13, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SCN5A c.560C>G (p.Thr187Ser) results in a conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 245776 control chromosomes, predominantly at a frequency of 0.00012 within the Latino subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.560C>G has been reported in the literature in unspecified individuals affected with Brugada syndrome (Berthome_HR_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Arrhythmia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 30193851). ClinVar contains an entry for this variant (Variation ID: 532122). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
CardioboostCm	Benign	0.097
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	.;.;.;.;.;D;.;.;.;D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	.;T;T;T;T;T;T;.;T;T
M_CAP	Pathogenic	0.69	D
MetaRNN	Uncertain	0.69	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	0.41	.;N;.;.;.;N;.;.;.;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.4	D;D;D;D;D;D;D;D;D;.
REVEL	Pathogenic	0.81
Sift	Uncertain	0.014	D;D;D;D;D;D;D;D;D;.
Sift4G	Benign	0.24	T;T;T;T;T;T;T;T;T;T
Polyphen		0.39	B;D;.;B;.;D;D;.;.;.
Vest4		0.43
MutPred		0.61		Loss of catalytic residue at T187 (P = 0.0977);Loss of catalytic residue at T187 (P = 0.0977);Loss of catalytic residue at T187 (P = 0.0977);Loss of catalytic residue at T187 (P = 0.0977);Loss of catalytic residue at T187 (P = 0.0977);Loss of catalytic residue at T187 (P = 0.0977);Loss of catalytic residue at T187 (P = 0.0977);Loss of catalytic residue at T187 (P = 0.0977);Loss of catalytic residue at T187 (P = 0.0977);Loss of catalytic residue at T187 (P = 0.0977);
MVP		0.85
MPC		1.1
ClinPred		0.59	D
GERP RS		4.1
Varity_R		0.51
gMVP		0.88

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: rs199473558; hg19: chr3-38662385;