rs199473324

chr3-38550748-A-Gchr3-38550748-A-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_001099404.2(SCN5A):c.5624T>C(p.Met1875Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 9.32

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 17 ACMG points.

• PM1: In a helix (size 16) in uniprot entity SCN5A_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_001099404.2
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SCN5A
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.971
• PP5: Variant 3-38550748-A-G is Pathogenic according to our data. Variant chr3-38550748-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 68002.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2	c.5624T>C	p.Met1875Thr	missense_variant	28/28	ENST00000413689.6
SCN5A	NM_000335.5	c.5621T>C	p.Met1874Thr	missense_variant	28/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.5624T>C	p.Met1875Thr	missense_variant	28/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.5621T>C	p.Met1874Thr	missense_variant	28/28	1	NM_000335.5	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 04, 2024	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1875 of the SCN5A protein (p.Met1875Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with atrial fibrillation (PMID: 18929244). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 68002). 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: 18929244). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 27, 2016	The Met1875Thr mutation in the SCN5A gene has been reported in association with atrial fibrillation in multiple individuals from three generations of a Japanese family (Makiyama T et al., 2008). Six individuals had frequent premature atrial contractions (PACs) or atrial fibrillation, and only one individual had a prolonged QTc interval. Met1875Thr was absent from 210 Japanese control individuals in this study (Makiyama T et al., 2008). In addition, Met1875Thr was not observed in approximately 6,300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Met1875Thr results in a non-conservative amino acid substitution of a non-polar Methionine with a polar Threonine at a position that is highly conserved across species (Makiyama T et al., 2008). Mutations in nearby residues (Val1861Ile, Lys1872Asn, Arg1897Trp) have been reported in association with arrhythmia, further supporting the functional importance of this region of the protein. Functional studies showed a pronounced depolarized shift in steady-state inactivation and no persistent inward sodium currents, which is consistent with a unique gainof- function type of modulation (Makiyama T et al., 2008). -

Atrial fibrillation Other:1

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 Atrial fibrillation in the following publications (PMID:18929244). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
CardioboostArm	Uncertain	0.85
CardioboostCm	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
Cadd	Uncertain	25
Dann	Uncertain	0.99
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.97	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	0.89	D
PROVEAN	Pathogenic	-5.5	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	0.0040	D;D;D;D;D;D;D;D;D
Polyphen		0.92	P;D;.;P;.;B;P;.;.
Vest4		0.94
MutPred		0.84		.;.;Loss of helix (P = 0.0041);.;.;Loss of helix (P = 0.0041);.;.;.;
MVP		0.97
MPC		1.5
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.93
gMVP		0.98

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: rs199473324; hg19: chr3-38592239;