chr3-38597889-G-A
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Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP2PP3_Moderate
The NM_000335.5(SCN5A):c.2102C>T(p.Pro701Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000328 in 1,614,038 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. P701P) has been classified as Benign.
Frequency
Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000031 ( 0 hom. )
Consequence
SCN5A
NM_000335.5 missense
NM_000335.5 missense
Scores
11
7
2
Clinical Significance
Conservation
PhyloP100: 6.75
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
PM1
In a repeat II (size 270) in uniprot entity SCN5A_HUMAN there are 47 pathogenic changes around while only 2 benign (96%) in NM_000335.5
PM2
Very rare variant in population databases, with high coverage;
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, 0.899
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| SCN5A | NM_001099404.2 | c.2102C>T | p.Pro701Leu | missense_variant | 14/28 | ENST00000413689.6 | NP_001092874.1 | |
| SCN5A | NM_000335.5 | c.2102C>T | p.Pro701Leu | missense_variant | 14/28 | ENST00000423572.7 | NP_000326.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| SCN5A | ENST00000413689.6 | c.2102C>T | p.Pro701Leu | missense_variant | 14/28 | 5 | NM_001099404.2 | ENSP00000410257.1 | ||
| SCN5A | ENST00000423572.7 | c.2102C>T | p.Pro701Leu | missense_variant | 14/28 | 1 | NM_000335.5 | ENSP00000398266.2 |
Frequencies
GnomAD3 genomes 0.0000460 AC: 7AN: 152226Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000883 AC: 22AN: 249234Hom.: 0 AF XY: 0.0000592 AC XY: 8AN XY: 135202
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GnomAD4 exome AF: 0.0000315 AC: 46AN: 1461694Hom.: 0 Cov.: 31 AF XY: 0.0000289 AC XY: 21AN XY: 727132
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GnomAD4 genome 0.0000459 AC: 7AN: 152344Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4AN XY: 74500
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:7Benign:1Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:4
| Uncertain significance, no assertion criteria provided | provider interpretation | Stanford Center for Inherited Cardiovascular Disease, Stanford University | May 18, 2017 | We have seen this variant in one patient with Brugada type 1 pattern. Testing was performed at Invitae. Given the weak case data, its presence in individuals with diverse phenotypes, weak functional data, and enriched frequency in population databases, we consider this variant a variant of uncertain significance, likely benign and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Not including our case, the variant has been seen in at least 2 unrelated cases of LQTS and 1 case of atrial fibrillation. It has also been seen in no more than 3 individuals who have had genetic testing for either LQTS, Brugada or cardiomyopathy. No clinical information available on these individuals. There It has not been reported in any confirmed cases of Brugada syndrome. There is weak case data and no segregation data. Tan et al., 2006 (17088455) identified this variant in a 17yo with long QT syndrome and torsade de pointes recruited from the Netherlands. The variant was reported in 1 individual in the Familion compendium, which includes 2500 patients referred for clinical long QT genetic testing (Kapplinger et al 2009). 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). Zellerhoff et al. (2009) reports the variant in a 24yo female who has a QTc of 620ms, history of syncope, and atrial flutter/tachycardia. Itoh et al. (2015) reports one family in which two individuals carry this variant. Subjects were recruited from Europe and Japan on the basis that they had a "known pathogenic variant". The authors do not include clinical data and but do include obligate carriers (who may have been unaffected). Some of the authors overlap with the Tan paper, so the case may be redundant. Kapplinger et al. (2010) identified this variant in one patient referred for Brugada syndrome genetic testing. Similar to the group's 2009 paper, there is lack of clinical data. This case may also overlap with the 2009 paper. Maekawa et al.(2005) identified in this variant in one 60yo Japanese patient with atrial fibrillation. They specifically indicate that patients with LQTS and Brugada syndrome were not included in this study. Functional data suggest that the variant does not have an effect on sodium channel activity (Hoshi et al. 2014). The variant is been seen in 26 of 138,593 individuals 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. Specifically the variant has been seen in 12 of 17,209 Latino individuals (MAF = 0.03%), 13 of 63,340 European individuals (MAF = 0.01%), and 1 of 12,017 African individuals (0.004%). The average coverage at that site in gnomAD is 75x. Kapplinger et al (2015) reported this variant in one of their healthy controls. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2016 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 701 of the SCN5A protein (p.Pro701Leu). This variant is present in population databases (rs199473147, gnomAD 0.03%). This missense change has been observed in individual(s) with long QT syndrome (PMID: 15996170, 17088455, 19716085, 20129283). ClinVar contains an entry for this variant (Variation ID: 67713). 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. Experimental studies have shown that this missense change does not substantially affect SCN5A function (PMID: 24573164). 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. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 08, 2023 | Identified in association with cardiac arrhythmia, including LQTS (Tan et al., 2006; Kapplinger et al., 2009; Zellerhoff et al., 2009; Itoh et al., 2016), Brugada syndrome (Kapplinger et al., 2010), and atrial fibrillation (Maekawa et al., 2005); Identified in an individual from a cohort of individuals not selected for cardiomyopathy, arrhythmia, or family history of sudden cardiac death, who underwent exome sequencing and whose follow-up cardiac evaluation was negative for arrhythmia or cardiomyopathy (Ng et al., 2013); Patch clamp studies in HEK293 cells showed that p.(P701L), either expressed alone or co-expressed with wild-type SCN5A channels, had no significant impact on sodium currents compared to wild-type SCN5A channels expressed alone (Hoshi et al., 2014); 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: 19716085, 20129283, 17088455, 15996170, 26332594, 26669661, 28150151, 25904541, 30203441, 19017345, 24573164, 23861362) - |
Cardiac arrhythmia Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jul 29, 2024 | This missense variant replaces proline with leucine at codon 701 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. A functional study has shown that this variant does not cause significant change in sodium channel activity (PMID: 24573164). This variant has been reported in individuals affected with long QT syndrome (PMID: 17088455), arrhythmia (PMID: 15996170) and Brugada syndrome (PMID: 34856468), as well as in individuals referred for genetic testing for long QT syndrome and Brugada syndrome (PMID: 19716085, 20129283) and in a healthy control individual (PMID: 25904541). This variant has also been identified in 24/280634 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 27, 2023 | This missense variant replaces proline with leucine at codon 701 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. An experimental study has shown that this variant does not cause significant change in sodium channel activity (PMID: 24573164). This variant has been reported in individuals affected with long QT syndrome (PMID: 17088455), arrhythmia (PMID: 15996170), or Brugada syndrome (PMID: 34856468), in individuals referred for genetic testing for long QT syndrome and Brugada syndrome (PMID: 19716085, 20129283), and in a healthy control individual (PMID: 25904541). This variant has also been identified in 24/280634 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
SUDDEN INFANT DEATH SYNDROME;C1832680:Dilated cardiomyopathy 1E;C1837845:Sick sinus syndrome 1;C1859062:Long QT syndrome 3;C1879286:Progressive familial heart block, type 1A;C2751898:Ventricular fibrillation, paroxysmal familial, type 1;C3151464:Atrial fibrillation, familial, 10;C4551804:Brugada syndrome 1 Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Juno Genomics, Hangzhou Juno Genomics, Inc | - | PM2_Supporting+PP3_Moderate+PP2+PS4_Moderate - |
Long QT syndrome Uncertain:1
| Uncertain significance, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Apr 05, 2018 | - - |
Cardiovascular phenotype Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 29, 2023 | 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. - |
Congenital long QT syndrome 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 Long QT syndrome in the following publications (PMID:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
CardioboostCm
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
.;.;.;.;.;D;.;.;.
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
.;D;D;D;D;D;D;.;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
.;H;.;.;.;H;.;.;.
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D;D;D;D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D;D;D;D;D;D
Sift4G
Uncertain
D;D;D;D;T;D;D;T;T
Polyphen
D;D;.;D;.;D;D;.;.
Vest4
MVP
MPC
0.98
ClinPred
D
GERP RS
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at