ClinVar Genomic variation as it relates to human health
NM_000335.5(SCN5A):c.3206C>T (p.Thr1069Met)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Uncertain significance(3); Likely benign(3)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000335.5(SCN5A):c.3206C>T (p.Thr1069Met)
Variation ID: 67782 Accession: VCV000067782.22
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 38580953 (GRCh38) [ NCBI UCSC ] 3: 38622444 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jun 1, 2016 May 1, 2024 Jan 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000335.5:c.3206C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000326.2:p.Thr1069Met missense NM_001099404.2:c.3206C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001092874.1:p.Thr1069Met missense NM_001099405.2:c.3206C>T NP_001092875.1:p.Thr1069Met missense NM_001160160.2:c.3206C>T NP_001153632.1:p.Thr1069Met missense NM_001160161.2:c.3206C>T NP_001153633.1:p.Thr1069Met missense NM_001354701.2:c.3206C>T NP_001341630.1:p.Thr1069Met missense NM_198056.3:c.3206C>T NP_932173.1:p.Thr1069Met missense NC_000003.12:g.38580953G>A NC_000003.11:g.38622444G>A NG_008934.1:g.73720C>T NG_053884.1:g.2692G>A LRG_289:g.73720C>T LRG_289t1:c.3206C>T LRG_289p1:p.Thr1069Met Q14524:p.Thr1069Met - Protein change
- T1069M
- Other names
- p.T1069M:ACG>ATG
- Canonical SPDI
- NC_000003.12:38580952:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00020 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00006
Exome Aggregation Consortium (ExAC) 0.00012
The Genome Aggregation Database (gnomAD), exomes 0.00015
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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SCN5A | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3739 | 4175 | |
LOC110121269 | - | - | - | GRCh38 | - | 417 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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not provided (1) |
no classification provided
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- | RCV000058554.11 | |
Likely benign (2) |
criteria provided, single submitter
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Jan 16, 2024 | RCV000183027.15 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Jan 31, 2024 | RCV000766797.14 | |
Uncertain significance (1) |
criteria provided, single submitter
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May 28, 2019 | RCV000987211.9 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 9, 2023 | RCV001842330.11 | |
Likely benign (1) |
criteria provided, single submitter
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Dec 21, 2021 | RCV002321559.9 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Uncertain significance
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Brugada syndrome 1
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001136460.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Uncertain significance
(Jul 24, 2019)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000235435.12
First in ClinVar: Jul 05, 2015 Last updated: Mar 04, 2023 |
Comment:
Reported in individuals with LQTS or referred for LQTS genetic testing and in one infant with sudden unexplained death who also harbored additional variants in … (more)
Reported in individuals with LQTS or referred for LQTS genetic testing and in one infant with sudden unexplained death who also harbored additional variants in four other cardiac genes (Tester et al., 2005; Kapa et al., 2009; Kapplinger et al., 2009; Goldenberg et al., 2011; Kapplinger et al., 2015; Methner et al., 2016); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 67782; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 19716085, 27435932, 31737537, 15840476, 16731473, 19841300, 21185501, 25904541, 28150151, 22581653, 28988457) (less)
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Uncertain significance
(Feb 09, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cardiac arrhythmia
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV001349230.4
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces threonine with methionine at codon 1069 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces threonine with methionine at codon 1069 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals suspected of having long QT syndrome (PMID: 25904541). This variant has been identified in 37/246942 chromosomes (32/34364 Latino chromosomes) in the general population by the Genome Aggregation Database (gnomAD). The relatively high frequency of this variant in the general population suggests that this variant is unlikely to be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Likely benign
(Jan 31, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000545063.7
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
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Likely benign
(Jan 16, 2024)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004803483.1
First in ClinVar: Mar 30, 2024 Last updated: Mar 30, 2024 |
Comment:
Variant summary: SCN5A c.3206C>T (p.Thr1069Met) results in a non-conservative amino acid change located in the Sodium ion transport-associated domain of the encoded protein sequence. Three … (more)
Variant summary: SCN5A c.3206C>T (p.Thr1069Met) results in a non-conservative amino acid change located in the Sodium ion transport-associated domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 246942 control chromosomes, predominantly at a frequency of 0.00093 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 9 fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN5A causing Arrhythmia phenotype (0.0001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.3206C>T has been reported in the literature in individuals affected with Arrhythmia. These report(s) do not provide unequivocal conclusions about association of the variant with Arrhythmia.To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 31737537). ClinVar contains an entry for this variant (Variation ID: 67782). Based on the evidence outlined above, the variant was classified as likely benign. (less)
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Likely benign
(Dec 21, 2021)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002610404.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
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 … (more)
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. (less)
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Uncertain significance
(Apr 21, 2014)
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no assertion criteria provided
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000280472.1
First in ClinVar: Jun 01, 2016 Last updated: Jun 01, 2016 |
Comment:
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case … (more)
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Thr1069Met (T1069M; c.3206C>T) in exon 17 of the SCN5A gene (NM_198056.2) We do not believe there is enough evidence to call this variant “disease-causing” at this time. It may instead be a rare benign variant that is more common in individuals with Hispanic ancestry. It has only been published in one “case” of LQTS, and this individual was also Hispanic. Furthermore, there is no phenotype data available for that patient, and so we cannot confirm that the individual actually had LQTS. This variant has previously been reported in just one Hispanic individual (the ethnicity is important) who had genetic testing for LQTS through the Familion laboratory (Tester et al. 2005; Kapplinger et al. 2009, Kapa et al. 2009). There is no phenotype information available for this individual, and we cannot assume that they have a confirmed clinical diagnosis of LQTS. Of note, genetic testing for the 2500 Familion cases reported by Kapplinger et al (2009) have an unusually low yield of 36% (vs. 70% in cohorts with a firm diagnoses of long QT syndrome), which suggests that not all of these patients have a firm diagnosis. Also, these papers have a lack of clarity regarding which variants were seen with another pathogenic variant (9% of the cohort had multiple variants). This is a non-conservative amino acid change, resulting in the replacement of a polar Threonine with a nonpolar Methionine in interdomain linker II-III. The Threonine at this location is NOT conserved across vertebrate species, and in fact the default amino acid is a Methionine in alligators and in 2 species of bird. Variation at nearby residues (+/- 10 amino acids) has NOT been associated with LQTS except for at residue Ser1079, which may argue against the functional importance of this region of the protein: (HGMD professional version as of January 17, 2014; and GeneDx report). This site in the protein is also not conserved across paralogue proteins: http://cardiodb.org/Paralogue_Annotation/residue.php?gene=SCN5A&position=1069. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “Probably Damaging” with a score of 0.993. In total the variant has been seen in 15 published controls or individuals from publicly available population datasets. The p.Thr1069Met variant is overrepresented among “Latino” individuals in the ExAC dataset, which currently includes variant calls on ~60,000 individuals of multiple ethnic backgrounds (Latino, European (non-Finnish), Finnish, South Asian, African & East Asian). It is present in 11 out of 5,749 Latinos in that database, which is an allele frequency of 0.1%. This estimates that ~2 out of every 1000 Latinos would carry the variant, which is a higher incidence than the overall estimated incidence of LQTS (1 in 2500 people). This variant is otherwise present in only 1 South Asian individual (out of 6,634) and 2 Caucasian individuals (out of 35,669). These individuals took part in a range of disease-specific and population genetic studies, and the curators made an effort to exclude individuals with severe pediatric diseases. There is only one individual with this variant listed in 1000 Genomes (http://browser.1000genomes.org/index.htm) as of 3/26/2015, and this individual also has Mexican ancestry. The variant was not observed in published controls, including 1300 from Kapplinger et al. 2009 (143 of them Hispanic). There is also no variation at this residue listed in the NHLBI Exome Sequencing Project dataset (http://evs.gs.washington.edu/EVS/), which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals who are NOT ethnicity-matched to our patient (who has Hispanic ancestry). The phenotype of the ESP individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. (less)
Number of individuals with the variant: 2
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not provided
(-)
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no classification provided
Method: literature only
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Congenital long QT syndrome
Affected status: unknown
Allele origin:
germline
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Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust
Accession: SCV000090074.3
First in ClinVar: Oct 22, 2013 Last updated: Oct 09, 2016 |
Comment:
This variant has been reported as associated with Long QT syndrome in the following publications (PMID:15840476;PMID:19716085;PMID:19841300). This is a literature report, and does not necessarily … (more)
This variant has been reported as associated with Long QT syndrome in the following publications (PMID:15840476;PMID:19716085;PMID:19841300). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls. | Walsh R | Genetics in medicine : official journal of the American College of Medical Genetics | 2021 | PMID: 32893267 |
Variant panorama in 1,385 index patients and sensitivity of expanded next-generation sequencing panels in arrhythmogenic disorders. | Marschall C | Cardiovascular diagnosis and therapy | 2019 | PMID: 31737537 |
Enhanced Classification of Brugada Syndrome-Associated and Long-QT Syndrome-Associated Genetic Variants in the SCN5A-Encoded Na(v)1.5 Cardiac Sodium Channel. | Kapplinger JD | Circulation. Cardiovascular genetics | 2015 | PMID: 25904541 |
Genetic testing for long-QT syndrome: distinguishing pathogenic mutations from benign variants. | Kapa S | Circulation | 2009 | PMID: 19841300 |
Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test. | Kapplinger JD | Heart rhythm | 2009 | PMID: 19716085 |
Allelic variants of SCN5A and risk of sudden cardiac arrest in patients with coronary artery disease. | Stecker EC | Heart rhythm | 2006 | PMID: 16731473 |
Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing. | Tester DJ | Heart rhythm | 2005 | PMID: 15840476 |
Text-mined citations for rs199473187 ...
HelpRecord last updated May 12, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.