rs45563942

chr3-38550865-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 4P and 3B. PM2 PP2 PP3 BP4_Moderate BP6

The NM_001099404.2(SCN5A):c.5507T>C(p.Ile1836Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000143 in 1,613,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. I1836I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000089 (0 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:8 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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SCN5A
• PP3: Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_noAF, Cadd, CardioboostArm, M_CAP, phyloP100way_vertebrate, PrimateAI, PROVEAN, REVEL [when FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.12645057).
• BP6: Variant 3-38550865-A-G is Benign according to our data. Variant chr3-38550865-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 39445.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, not_provided=1, Uncertain_significance=1}. Variant chr3-38550865-A-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2	c.5507T>C	p.Ile1836Thr	missense_variant	28/28	ENST00000413689.6
SCN5A	NM_000335.5	c.5504T>C	p.Ile1835Thr	missense_variant	28/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.5507T>C	p.Ile1836Thr	missense_variant	28/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.5504T>C	p.Ile1835Thr	missense_variant	28/28	1	NM_000335.5	A1

Frequencies

GnomAD3 genomes AF: 0.000657 AC: 100 AN: 152140 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00237

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000225 AC: 56 AN: 249380 Hom.: 0 AF XY: 0.000170 AC XY: 23 AN XY: 135276

Gnomad AFR exome AF: 0.00329

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000889 AC: 130 AN: 1461598 Hom.: 0 Cov.: 32 AF XY: 0.0000688 AC XY: 50 AN XY: 727078

Gnomad4 AFR exome AF: 0.00346

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000994

GnomAD4 genome AF: 0.000657 AC: 100 AN: 152258 Hom.: 0 Cov.: 33 AF XY: 0.000698 AC XY: 52 AN XY: 74466

Gnomad4 AFR AF: 0.00236

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.0000921 Hom.: 0

Bravo AF: 0.000597

ESP6500AA AF: 0.00258 AC: 11

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000231 AC: 28

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2 Benign:8 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:4 Other:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
not provided, no classification provided	literature only	Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	-	This variant has been reported in the following publications (PMID:19841300;PMID:20129283;PMID:19412328). -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 04, 2023	Reported in at least one proband with DCM and segregated with disease in affected relatives; of note, this variant was reported as I1835T due to alternate nomenclature (Hershberger et al., 2008; Cheng et al., 2010); Also identified in an infant with sudden unexplained death at three months of age, though no family history or segregation studies were described (Methner et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15851227, 20129283, 24055113, 26332594, 25637381, 27896284, 25904541, 19841300, 27435932, 26746457, 19412328, 21167004) -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 20, 2018	The SCN5A c.5507T>C; p.Ile1836Thr variant (rs45563942, ClinVar variant ID 39445) has been reported to segregate with dilated cardiomyopathy in one family (Hershberger 2008), but was also detected in a healthy control individual (Kapa 2009), and several subsequent studies have concluded that the frequency of this variant in the population is inconsistent with a causative role in disease (Amendola 2015, Dorschner 2013, Nourhavesh 2016, Olfson 2015). This variant is listed in the genome Aggregation Database (gnomAD) with an African population frequency of 0.3% (identified on 73 out of 24,028 chromosomes). The isoleucine at position 1836 is highly conserved, considering 9 species, and computational analyses of the effects of the p.Ile1836Thr variant on protein structure and function predict a deleterious effect (SIFT: damaging, PolyPhen-2: possibly damaging). Based on the available information, the p.Ile1836Thr variant is likely to be benign. -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Dilated cardiomyopathy 1E Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 2008

- -

Primary dilated cardiomyopathy Uncertain:1

Uncertain significance, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Jul 13, 2020

Variant summary: SCN5A c.5507T>C (p.Ile1836Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00022 in 249380 control chromosomes, predominantly at a frequency of 0.0033 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 132-fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN5A causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.5507T>C was reported to co-segregate with cardiomyopathy in one African-American family (Hershberger_2008, Cheng_2010) but was also subsequently reported by different studies in multiple individuals without a cardiomyopathy phenotype (e.g. Kapplinger_2015, VanDriest_2016). Furthermore, experimental evidence demonstrated that expression of the variant alone in HEK293 cells did not cause any significant changes in biophysical properties compared to wild-type (Cheng_2010). A co-occurrence with a pathogenic variant has been reported (TTR c.424G>A, p.Val142Ile; Internal testing). Five ClinVar submitters (evaluation after 2014) cite the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

SCN5A-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 20, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 24, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Cardiac arrhythmia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Nov 26, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
CardioboostArm	Pathogenic	0.99
CardioboostCm	Uncertain	0.15
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Pathogenic	0.45
Cadd	Pathogenic	26
Dann	Uncertain	1.0
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.80	D
MetaRNN	Benign	0.13	T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	0.91	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-4.2	D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.016	D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.11	T;T;T;T;T;T;T;T;T
Polyphen		0.070	B;B;.;B;.;B;P;.;.
Vest4		0.95
MVP		0.90
MPC		1.6
ClinPred		0.072	T
GERP RS		4.8
Varity_R		0.83
gMVP		0.96

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: rs45563942; hg19: chr3-38592356;