3-38551441-C-T

Position:

chr3-38551441-C-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_000335.5(SCN5A):c.4928G>A(p.Arg1643His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,964 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1643C) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

SCN5A
NM_000335.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:15O:1

Conservation

PhyloP100: 7.89

Variant links:

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]

SCN5A links:

SCN5A (HGNC:):

SCN5A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 19 ACMG points.

PM1

In a helix (size 10) in uniprot entity SCN5A_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000335.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-38551442-G-A is described in Lovd as [Pathogenic].

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SCN5A. . Gene score misZ 2.7504 (greater than the threshold 3.09). Trascript score misZ 4.8279 (greater than threshold 3.09). GenCC has associacion of gene with 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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.99

PP5

Variant 3-38551441-C-T is Pathogenic according to our data. Variant chr3-38551441-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 9369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38551441-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_001099404.2 linkuse as main transcript	c.4931G>A	p.Arg1644His	missense_variant	28/28	ENST00000413689.6	NP_001092874.1	Q14524H9KVD2
SCN5A	NM_000335.5 linkuse as main transcript	c.4928G>A	p.Arg1643His	missense_variant	28/28	ENST00000423572.7	NP_000326.2	Q14524-2Q86V90

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6 linkuse as main transcript	c.4931G>A	p.Arg1644His	missense_variant	28/28	5	NM_001099404.2	ENSP00000410257.1		H9KVD2
SCN5A	ENST00000423572.7 linkuse as main transcript	c.4928G>A	p.Arg1643His	missense_variant	28/28	1	NM_000335.5	ENSP00000398266.2		Q14524-2

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727240

show subpopulations

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:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152078

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74278

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 04, 2023	PP1_strong, PP3, PM1, PM2, PS3_supporting, PS4_moderate -
Likely pathogenic, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Sep 22, 2017	SCN5A Arg1644His c.4931G>A in exon 28, (NM_198056.2, ENST00000303395) hg19 chr3-38592932-C-T SCICD Classification: Likely pathogenic, based on adequate case data, absence in population datasets, and location in region enriched for disease variants. We do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Case data: -1 case of LQTS in our center - at least 3 cases of LQTS published (below) - 3 cases "referred for LQTS genetic testing", phenotypes unavailable (below) LQTS cases in the literature: Wang et al., 1995 (PMID 8541846) - segregated in a mother and son with long QT (recruited in Europe, North America, overlapping authors with Splawski et al so may be redundant) Splawski et al., 2000 (PMID 10973849)- seen in 2 families with long QT (recruited in Europe, North America, overlapping authors with Wang et al so may be redundant) Millat et al., 2009 (PMID 19026623) - seen in 1 male with long QT (study done in France, no overlap with other authors, recruitment location not noted). Cases "referred for LQTS genetic testing": Tester et al., 2005 (PMID 15840476) - Seen in 2 unrelated people referred for long QT testing, Ackerman's long QT testing series (tested in his lab), probably not overlapping with Kapplinger et al. Kapplinger et al., 2009 - seen in 1 patient referred for long QT testing at Familion. Those cases likely overlap with the data in Kapa et al (2009) since these are all from Ackerman's group and use data from his cohort and from the Familion cohort. Of note in considering the cases reported by Kapplinger et al (2009) is the lack of phenotypic data on this cohort, the low yield of 36% (vs. 70% in cohorts with firm diagnoses of long QT), and the lack of clarity regarding which variants were seen with another variant (9% of the cohort had multiple variants). Segregation data: segregated with disease in 2 family members (Wang et al., 1995) Functional data: This residue is located in the S4 voltage sensor transmembrane helix of domain IV of the protein. These region is enriched for variants seen in cases vs controls (https://www.cardioclassifier.org/Classifier). Dumaine et al., 1996 (PMID 8620612): heterologous expression in Xenopus oocytes showed inactivation resistance Wang et al., 1996 (PMID 8917568) - heterologous expression in human HEK 293 tsA-201 cells showed showed sustained inward current and non-zero variance, indicating continued channel gating, at times later than 20 msec. Paralogue data from cardiodb: Several variants at position 1644 in paralogous proteins have been reported to be disease causing. A corresponding Arginine to Histidine substitution was reported to cause cryptogenic focal epilepsy in the SCN1A gene (one de novo case). Arginine to Cysteine substitutions at the corresponding amino acids have also been reported in SCN1A (to cause generalized epilepsy with febrile seizures) and CACNA1A (episodic ataxia 2). Conservation data: Per the lab report, The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. There is no variation at codon 1644 listed in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. Per Varsome.org, the average coverage at that site in genomes is mean 32.9x, median 32x, and 93.75% of samples have >20x coverage; in exomes it is mean 96.8x, median 100x, and 100% of samples have >20x coverage. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 08, 2022	Not observed at significant frequency in large population cohorts (gnomAD); Located near the cytoplasmic end of the S4 segment of domain IV; Electrophysiological studies in both Xenopus oocytes and mammalian cell lines have shown that R1644H alters the functional properties of the SCN5A channel (Dumaine et al., 1996; Wang et al., 1996); 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: 14753626, 10508990, 25904541, 18849657, 26669661, 28721524, 31983221, 8620612, 15840476, 15051636, 19841300, 10973849, 15121794, 11273715, 8541846, 26803770, 28220464, 25661095, 28341781, 28412158, 25294783, 29691127, 28573431, 28265756, 28150151, 19026623, 29766885, 31737537, 32383558, 31057083, 8917568, 35052356, 30369311) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	SCN5A: PM1, PM2, PM5, PP1, PP3, PS3:Supporting, PS4:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 04, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1644 of the SCN5A protein (p.Arg1644His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with long QT syndrome (PMID: 8541846, 10973849, 19026623, 19841300). ClinVar contains an entry for this variant (Variation ID: 9369). 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: 8620612, 8917568). For these reasons, this variant has been classified as Pathogenic. -

Long QT syndrome 3

Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 10, 1995	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	Jan 12, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	May 13, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM2_Supporting+PS3_Moderate+PS4_Moderate+PP1_Strong+PP4 -

Congenital long QT syndrome

Pathogenic:2Other: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 Long QT syndrome in the following publications (PMID:8541846;PMID:10973849;PMID:15051636;PMID:15840476;PMID:19841300;PMID:8620612;PMID:8917568). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 27, 2019	The p.Arg1644His variant in SCN5A has been reported in at least 7 individuals with long QT syndrome (LQTS) and segregated with disease in >10 affected individuals from 2 families (Wang 1995, Wattanasirichaigoon 1999, Splawski 2000, Westenskow 2004, Millat 1009, Kapa 2009, Malan 2016, Anderson 2017, Nieto-Marin 2018). It was also identified in 1 individual with Brugada syndrome (Yamagata 2017). This variant was absent from large population studies but has been reported in ClinVar as pathogenic by multiple clinical laboratories (Variation ID # 9369). In vitro functional studies and computational prediction tools support an impact on protein function (Wang 1996, Dumaine 1996, Malan 2016). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant LQTS. ACMG/AMP criteria applied: PP1_Strong, PM2, PS3_Moderate, PS4_Moderate, PP3. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 18, 2024	This missense variant replaces arginine with histidine at codon 1644 of the SCN5A protein. This variant is also known as c.4928G>A (p.Arg1643His) based on a different transcript NM_000335.5. This variant is found within a highly conserved region of the transmembrane domain DIV. Rare nontruncating variants in this region have been shown to be significantly overrepresented in individuals with Brugada syndrome and long QT syndrome (PMID: 32893267). Functional studies have shown that this variant causes a persistent late inward current when expressed in human kidney cell line and in Xenopus oocytes (PMID: 8620612, 8917568). Induced pluripotent stem cells derived from a carrier individual exhibited accelerated recovery from inactivation of sodium currents, action potential prolongation, and a high incidence of early after depolarizations (PMID: 26803770). This variant has been reported in over ten unrelated individuals affected with long QT syndrome (PMID: 8541846, 1097384, 15051636, 19026623, 19841300, 21185501, 25294783, 26803770, 27566755, 29691127, 30369311, 32383558, 32893267, 32931730, 35052356), and in individuals affected with Brugada syndrome (PMID: 32893267), dilated cardiomyopathy (PMID: 31983221), and idiopathic ventricular fibrillation (PMID: 31057083). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

SCN5A-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

This variant has been previously reported as a heterozygous change in patients with long QT syndrome (PMID: 8541846, 28341781, 19026623, 19841300, 31737537). In vitro functional studies of p.Arg1644His showed increased persistent sodium currents compared to the wild-type channels (PMID: 8620612, 8917568). It is absent from the gnomAD population database and thus is presumed to be rare. The c.4931G>A (p.Arg1644His) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. A different amino acid change at the same codon (c.4930C>T, p.Arg1644Cys) has also been reported in individuals with long QT syndrome (PMID: 16344400, 19716085). Based on the available evidence, the c.4931G>A (p.Arg1644His) variant is classified as Pathogenic. -

Long QT syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Oct 24, 2022

Variant summary: SCN5A c.4931G>A (p.Arg1644His) results in a non-conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251476 control chromosomes. c.4931G>A has been reported in the literature in a large family with congenital LQTS (Malan_2016) and in multiple other individuals affected with Long QT Syndrome (example: Westenskow_2004 and Gibbs_2018 etc.). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant causes a sustained, non-inactivating inward current and exhibits prolonged action potential durations and increased recovery from inactivation (Dumaine_1996, Wang_1996, Malan_2016). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=5) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 23, 2023

The p.R1644H pathogenic mutation (also known as c.4931G>A), located in coding exon 27 of the SCN5A gene, results from a G to A substitution at nucleotide position 4931. The arginine at codon 1644 is replaced by histidine, an amino acid with highly similar properties. This mutation was originally detected in a mother and son affected with long QT syndrome (LQTS) (Wang Q et al. Hum Mol Genet. 1995;4(9):1603-7). Other studies demonstrated disruption of inactivation in channels expressed in a human cell line and in Xenopus oocytes; p.R1644H showed sustained inward current predicted to account for the long QT defect, but findings suggested p.R1644H may be less severe than other alterations studied (Dumaine R et al. Circ Res. 1996;78(5):916-24; Wang DW et al. Proc Natl Acad Sci U.S.A. 1996;93(23):13200-5). In a study of compound mutations as a common cause of severe LQTS, p.R1644H was detected in the father and brother of a child with sudden death who also had a variant in the KCNE1 gene (Westenskow P et al. Circulation. 2004;109(15):1834-41). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Cardiac arrhythmia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Apr 25, 2023

This missense variant replaces arginine with histidine at codon 1644 of the SCN5A protein. This variant is also known as c.4928G>A (p.Arg1643His) based on a different transcript NM_000335.5. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant is found within a highly conserved region of the transmembrane domain DIV. Rare nontruncating variants in this region have been shown to be significantly overrepresented in individuals with long QT syndrome (PMID: 32893267). Functional studies have shown that this variant causes a persistent late inward current when expressed in human kidney cell line and in Xenopus oocytes (PMID: 8620612, 8917568). Induced pluripotent stem cells derived from a carrier individual exhibited accelerated recovery from inactivation of sodium currents, action potential prolongation, and a high incidence of early after depolarizations (PMID: 26803770). This variant has been reported in over ten unrelated individuals affected with long QT syndrome (PMID: 8541846, 1097384, 15051636, 19026623, 19841300, 21185501, 25294783, 26803770, 27566755, 29691127, 30369311, 32383558, 32893267, 32931730, 35052356), and in individuals affected with Brugada syndrome (PMID: 32893267), dilated cardiomyopathy (PMID: 31983221), and idiopathic ventricular fibrillation (PMID: 31057083). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

CardioboostCm

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.98

.;.;.;.;.;D;.;.;.

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.95

.;D;D;D;D;D;D;.;D

M_CAP

Pathogenic

0.93

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.7

.;.;.;.;.;H;.;.;.

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-4.6

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

Benign

0.070

T;T;T;T;T;T;T;T;T

Polyphen

1.0

D;D;.;D;.;D;D;.;.

Vest4

0.91

MutPred

0.96

.;.;Loss of MoRF binding (P = 0.025);.;.;Loss of MoRF binding (P = 0.025);.;.;.;

MVP

1.0

MPC

1.6

ClinPred

1.0

GERP RS

4.5

Varity_R

0.84

gMVP

0.99

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over