3-38620894-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PS1 PM2 PM5 PP2

The NM_001099404.2(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 same amino acid change has been previously reported as Pathogenicin Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T187A) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• 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 9 ACMG points.

• PS1: Transcript NM_001099404.2 (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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-38620895-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 222801.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.
• PP2: Missense variant where missense usually causes diseases, SCN5A

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2	c.560C>G	p.Thr187Ser	missense_variant	5/28	ENST00000413689.6
SCN5A	NM_000335.5	c.560C>G	p.Thr187Ser	missense_variant	5/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.560C>G	p.Thr187Ser	missense_variant	5/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.560C>G	p.Thr187Ser	missense_variant	5/28	1	NM_000335.5	A1

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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 09, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 06, 2023	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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
CardioboostArm	Uncertain	0.68
CardioboostCm	Benign	0.097
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	0.11
Cadd	Uncertain	26
Dann	Uncertain	1.0
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.99	D
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
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
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;