ClinVar Genomic variation as it relates to human health
NM_003098.3(SNTA1):c.770C>G (p.Ala257Gly)
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(2); Benign(4); Likely benign(5)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_003098.3(SNTA1):c.770C>G (p.Ala257Gly)
Variation ID: 191548 Accession: VCV000191548.36
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 20q11.21 20: 33412714 (GRCh38) [ NCBI UCSC ] 20: 32000520 (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 8, 2015 Mar 16, 2024 Jan 22, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003098.3:c.770C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003089.1:p.Ala257Gly missense NC_000020.11:g.33412714G>C NC_000020.10:g.32000520G>C NG_011622.1:g.36179C>G LRG_332:g.36179C>G LRG_332t1:c.770C>G LRG_332p1:p.Ala257Gly Q13424:p.Ala257Gly - Protein change
- A257G
- Other names
- -
- Canonical SPDI
- NC_000020.11:33412713:G:C
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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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0.00100 (C)
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Allele frequency
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The frequency of the allele represented by this VCV record.
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00200
The Genome Aggregation Database (gnomAD) 0.00217
1000 Genomes Project 30x 0.00094
1000 Genomes Project 0.00100
Trans-Omics for Precision Medicine (TOPMed) 0.00178
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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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
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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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SNTA1 | - | - |
GRCh38 GRCh37 |
400 | 498 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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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Benign/Likely benign (3) |
criteria provided, multiple submitters, no conflicts
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Jan 22, 2024 | RCV000171774.13 | |
Likely benign (1) |
criteria provided, single submitter
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May 16, 2018 | RCV000247418.5 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Jan 15, 2021 | RCV000191018.16 | |
Benign (1) |
criteria provided, single submitter
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Aug 22, 2023 | RCV000990299.4 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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May 8, 2023 | RCV001256962.8 | |
Benign (3) |
criteria provided, single submitter
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May 21, 2019 | RCV001706109.5 | |
Likely benign (1) |
criteria provided, single submitter
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Mar 5, 2020 | RCV003917588.1 |
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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Likely benign
(Jun 24, 2013)
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criteria provided, single submitter
Method: research
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Long QT syndrome
Affected status: unknown
Allele origin:
unknown
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Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Study: ClinSeq
Accession: SCV000050786.1 First in ClinVar: Jun 08, 2015 Last updated: Jun 08, 2015 |
Number of individuals with the variant: 3
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Likely benign
(Jul 08, 2016)
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criteria provided, single submitter
Method: clinical testing
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Long QT syndrome 12
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Study: VKGL Data-share Consensus
Accession: SCV000743435.1 First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
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Uncertain significance
(Jan 15, 2021)
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criteria provided, single submitter
Method: clinical testing
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Long QT syndrome 12
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000605231.3
First in ClinVar: Sep 30, 2017 Last updated: Jan 08, 2022 |
Comment:
The SNTA1 c.770C>G; p.Ala257Gly variant (rs56157422) is reported in the literature in individuals affected with long QT syndrome (Wu 2008) and carriers of the variant … (more)
The SNTA1 c.770C>G; p.Ala257Gly variant (rs56157422) is reported in the literature in individuals affected with long QT syndrome (Wu 2008) and carriers of the variant have been reported to have a slightly longer QTc interval than non-carriers (Ghouse 2015). However, this variant is also reported in healthy controls in combination with p.Pro74Leu (Cheng 2009), and functional studies suggest that the p.Pro74Leu variant rescues altered channel activity of the p.Ala257Gly variant alone (Cheng 2011). The p.Ala257Gly variant is reported in ClinVar (Variation ID: 191548), and is found in the non-Finnish European population with an allele frequency of 0.34% (442/128,676 alleles, including 3 homozygotes) in the Genome Aggregation Database. The alanine at codon 257 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.357). Due to conflicting information, the clinical significance of the p.Ala257Gly variant is uncertain at this time. References: Cheng J et al. Alpha1-syntrophin mutations identified in sudden infant death syndrome cause an increase in late cardiac sodium current. Circ Arrhythm Electrophysiol. 2009 Dec;2(6):667-76. Cheng J et al. LQTS-associated mutation A257G in a1-syntrophin interacts with the intragenic variant P74L to modify its biophysical phenotype. Cardiogenetics. 2011 Oct 25;1(1). pii: 136. Ghouse J et al. Rare genetic variants previously associated with congenital forms of long QT syndrome have little or no effect on the QT interval. Eur Heart J. 2015 Oct 1;36(37):2523-9. Wu G et al. Alpha-1-syntrophin mutation and the long-QT syndrome: a disease of sodium channel disruption. Circ Arrhythm Electrophysiol. 2008 Aug;1(3):193-201. (less)
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Likely benign
(May 16, 2018)
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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: SCV000318140.6
First in ClinVar: Oct 02, 2016 Last updated: Nov 29, 2022 |
Comment:
This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, … (more)
This alteration is classified as likely benign based on a combination of the following: 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)
Number of individuals with the variant: 1
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Benign
(May 21, 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: SCV001942583.2
First in ClinVar: Sep 29, 2021 Last updated: Mar 04, 2023 |
Comment:
This variant is associated with the following publications: (PMID: 25956966, 24319568, 19684871, 26159999, 16252003, 20009079, 25650408, 28988457, 29714131)
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Uncertain significance
(May 08, 2023)
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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: SCV001623428.2
First in ClinVar: May 23, 2021 Last updated: Jun 24, 2023 |
Comment:
Variant summary: SNTA1 c.770C>G (p.Ala257Gly) results in a non-conservative amino acid change located in the Pleckstrin homology domain (IPR001849) of the encoded protein sequence. Four … (more)
Variant summary: SNTA1 c.770C>G (p.Ala257Gly) results in a non-conservative amino acid change located in the Pleckstrin homology domain (IPR001849) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0018 in 251372 control chromosomes in the gnomAD database, including 5 homozygotes. The observed variant frequency is approximately 525.12 fold of the estimated maximal expected allele frequency for a pathogenic variant in SNTA1 causing Long QT Syndrome phenotype (3.3e-06), strongly suggesting that the variant is benign. c.770C>G has been reported in the literature along with another SNTA1 variant, c.221C>T (p.Pro74Leu) in sequencing studies of individuals affected with Long QT Syndrome/Arrhythmia and/or in SIDS cohorts (example, Wu_2008, Ghouse_2015, Cheng_2009, Broendberg_2018). These data indicate that the variant may be associated with disease. At-least one co-occurrence with another pathogenic variant causative of Arrhythmia has been observed at our laboratory (KCNQ1 c.1686G>T, p.Arg562Ser), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a gain of function of the cardiac sodium channel (hNav1.5) (Wu_2008). Another study showed no damaging effect of this variant when present in conjunction with p.Pro74Leu. This variant combination reversed the peak sodium current and window current induced by the p.Arg257Gly variant alone (Cheng_2011). The following publications have been ascertained in the context of this evaluation (PMID: 23861362, 20009079, 24319568, 19684871, 29343803, 26159999). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign, n=2; likely benign, n=3; VUS, n=2). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. (less)
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Benign
(Aug 22, 2023)
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criteria provided, single submitter
Method: clinical testing
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Long QT syndrome 1
Affected status: unknown
Allele origin:
germline
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Mendelics
Accession: SCV001141232.2
First in ClinVar: Jan 09, 2020 Last updated: Aug 25, 2023 |
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Benign
(Jan 08, 2024)
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criteria provided, single submitter
Method: research
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Long QT syndrome
Affected status: yes
Allele origin:
paternal
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Dept of Medical Biology, Uskudar University
Accession: SCV004022006.2
First in ClinVar: Jul 29, 2023 Last updated: Jan 26, 2024 |
Comment:
Criteria: PP3, BS1, BS2
Number of individuals with the variant: 1
Sex: male
Ethnicity/Population group: Turkish
Geographic origin: Turkey
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Benign
(Jul 09, 2019)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: yes
Allele origin:
germline
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Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV001433501.1
First in ClinVar: Sep 27, 2020 Last updated: Sep 27, 2020 |
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Likely benign
(Jan 22, 2024)
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criteria provided, single submitter
Method: clinical testing
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Long QT syndrome
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000563491.8
First in ClinVar: Jun 08, 2015 Last updated: Feb 20, 2024 |
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Likely benign
(Mar 05, 2020)
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criteria provided, single submitter
Method: clinical testing
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SNTA1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004731520.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
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).
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Pathogenic
(Aug 01, 2008)
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no assertion criteria provided
Method: literature only
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LONG QT SYNDROME 12
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000245994.1
First in ClinVar: Sep 29, 2015 Last updated: Sep 29, 2015 |
Comment on evidence:
In 3 unrelated patients with long QT syndrome (LQT12; 612955), Wu et al. (2008) identified heterozygosity for an ala257-to-gly (A257G) substitution at a highly conserved … (more)
In 3 unrelated patients with long QT syndrome (LQT12; 612955), Wu et al. (2008) identified heterozygosity for an ala257-to-gly (A257G) substitution at a highly conserved residue in the SNTA1 protein. The mutation was not detected in 400 ethnically matched alleles. In 2 women, the change arose de novo, as it was not present in their unaffected parents, who had normal electrocardiograms. The third patient was a 17-year-old boy, whose sister, mother, maternal uncle, and maternal grandmother were also affected and heterozygous for the mutation; affected members of this family were also heterozygous for a variant of unknown significance in the KCNQ1 gene (607542), IVS7+5G-A. Electrophysiologic analysis in transfected HEK293 cells suggested that A257G mutant channels exhibit a gain of function through 3 mechanisms: increase of channel availability by leftward shift of activation kinetics, delay of current decay, and increase in current density. (less)
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001922034.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
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Benign
(-)
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no assertion criteria provided
Method: clinical testing
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not specified
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001952846.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001974708.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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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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Targeted next generation sequencing in a young population with suspected inherited malignant cardiac arrhythmias. | Broendberg AK | European journal of human genetics : EJHG | 2018 | PMID: 29343803 |
Rare genetic variants previously associated with congenital forms of long QT syndrome have little or no effect on the QT interval. | Ghouse J | European heart journal | 2015 | PMID: 26159999 |
Stimulant therapy in children with attention-deficit/hyperactivity disorder and concomitant long QT syndrome: A safe combination? | Rohatgi RK | Heart rhythm | 2015 | PMID: 25956966 |
Testing the burden of rare variation in arrhythmia-susceptibility genes provides new insights into molecular diagnosis for Brugada syndrome. | Le Scouarnec S | Human molecular genetics | 2015 | PMID: 25650408 |
Interpreting secondary cardiac disease variants in an exome cohort. | Ng D | Circulation. Cardiovascular genetics | 2013 | PMID: 23861362 |
LQTS-associated mutation A257G in α1-syntrophin interacts with the intragenic variant P74L to modify its biophysical phenotype. | Cheng J | Cardiogenetics | 2011 | PMID: 24319568 |
Alpha1-syntrophin mutations identified in sudden infant death syndrome cause an increase in late cardiac sodium current. | Cheng J | Circulation. Arrhythmia and electrophysiology | 2009 | PMID: 20009079 |
alpha-1-syntrophin mutation and the long-QT syndrome: a disease of sodium channel disruption. | Wu G | Circulation. Arrhythmia and electrophysiology | 2008 | PMID: 19684871 |
Text-mined citations for rs56157422 ...
HelpRecord last updated Mar 17, 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.