ClinVar Genomic variation as it relates to human health
NM_000218.3(KCNQ1):c.569G>T (p.Arg190Leu)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000218.3(KCNQ1):c.569G>T (p.Arg190Leu)
Variation ID: 67084 Accession: VCV000067084.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.5 11: 2570719 (GRCh38) [ NCBI UCSC ] 11: 2591949 (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 Oct 9, 2016 Apr 20, 2024 Oct 13, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000218.3:c.569G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000209.2:p.Arg190Leu missense NM_001406836.1:c.569G>T NP_001393765.1:p.Arg190Leu missense NM_001406837.1:c.299G>T NP_001393766.1:p.Arg100Leu missense NM_181798.2:c.188G>T NP_861463.1:p.Arg63Leu missense NR_040711.2:n.462G>T NC_000011.10:g.2570719G>T NC_000011.9:g.2591949G>T NG_008935.1:g.130729G>T LRG_287:g.130729G>T LRG_287t1:c.569G>T LRG_287p1:p.Arg190Leu LRG_287t2:c.188G>T LRG_287p2:p.Arg63Leu P51787:p.Arg190Leu - Protein change
- R190L, R63L, R100L
- Other names
- p.R190L:CGG>CTG
- Canonical SPDI
- NC_000011.10:2570718:G:T
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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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Allele frequency
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The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00001
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
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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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KCNQ1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh38 GRCh37 |
1696 | 2580 |
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
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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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Likely pathogenic (2) |
criteria provided, single submitter
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Mar 22, 2019 | RCV000057707.12 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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May 3, 2023 | RCV000182299.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 13, 2023 | RCV000698459.15 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Feb 27, 2023 | RCV000678947.11 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Feb 1, 2023 | RCV001841685.11 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Aug 25, 2022 | RCV002345367.8 |
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
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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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Pathogenic
(Apr 04, 2018)
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criteria provided, single submitter
Method: clinical testing
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Long QT syndrome 1
Affected status: yes
Allele origin:
unknown
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Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues
Accession: SCV000805161.1
First in ClinVar: Sep 14, 2018 Last updated: Sep 14, 2018 |
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Likely pathogenic
(Aug 25, 2022)
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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: SCV002652490.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.R190L variant (also known as c.569G>T), located in coding exon 3 of the KCNQ1 gene, results from a G to T substitution at nucleotide … (more)
The p.R190L variant (also known as c.569G>T), located in coding exon 3 of the KCNQ1 gene, results from a G to T substitution at nucleotide position 569. The arginine at codon 190 is replaced by leucine, an amino acid with dissimilar properties. In a study of long QT syndrome (LQTS) clinical genetic testing, this alteration was reported in one patient; however, clinical details were limited (Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303). This alteration was also reported in homozygous state in two sisters with LQTS, one of whom was also revealed to have subclinical bilateral sensorineural hearing impairment. Their asymptomatic parents were both heterozygous for this alteration and showed prolonged QTc upon stress test (Kanovsky J et al. Heart Rhythm, 2010 Apr;7:531-3). In vitro studies suggested that this alteration would affect channel activity (Eckey K et al. J. Biol. Chem., 2014 Aug;289:22749-58). 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 majority of available evidence to date, this variant is likely to be pathogenic. (less)
Number of individuals with the variant: 1
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Pathogenic
(Feb 27, 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:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV003921067.1
First in ClinVar: May 06, 2023 Last updated: May 06, 2023 |
Comment:
_x000D_ Criteria applied: PM5_STR, PS4_MOD, PM1, PM2_SUP, PP3
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Likely pathogenic
(May 03, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV004026373.1
First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023 |
Comment:
PP3, PM2_SUP
Observation 1: Observation 2: Observation 3: |
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Pathogenic
(Oct 13, 2023)
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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: SCV000827124.7
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 190 of the KCNQ1 protein (p.Arg190Leu). … (more)
This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 190 of the KCNQ1 protein (p.Arg190Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with long QT Syndrome (PMID: 19716085, 20138589, 31737537, 32383558; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 67084). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KCNQ1 protein function. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 24947509). This variant disrupts the p.Arg190 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8528244, 10376919, 10728423, 20660394). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Feb 01, 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: SCV001352305.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces arginine with leucine at codon 190 of the KCNQ1 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces arginine with leucine at codon 190 of the KCNQ1 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). A functional study has suggested that this missense variant may affect potassium channel function (PMID: 24947509). This variant has been reported in heterozygous state in an individual suspected of having long QT syndrome (PMID: 19716085). This variant has also been reported in homozygosity in two sisters, one affected with Jervell and Lange-Nielsen syndrome and the other one with Romano-Ward syndrome. Their heterozygous parents were asymptomatic but showed pathological QTs during the stress test (PMID: 20138589). This variant has been identified in 1/249462 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different missense variants occurring at the same codon, p.Arg190Gln and p.Arg190Trp are known to be disease-causing (ClinVar variation ID: 3117, 53070), indicating that arginine at this position is important for KCNQ1 protein function. Based on available evidence, this variant is classified as Likely Pathogenic. (less)
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Likely Pathogenic
(Mar 22, 2019)
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criteria provided, single submitter
Method: clinical testing
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Congenital long QT syndrome
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004847649.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Arg190Leu variant in KCNQ1 has been reported in 1 individual referred for LQTS genetic testing (Kapplinger 2009). In addition, it was identified in the … (more)
The p.Arg190Leu variant in KCNQ1 has been reported in 1 individual referred for LQTS genetic testing (Kapplinger 2009). In addition, it was identified in the homozygous state in 2 sisters from a consanguineous family with a severe presentation of LQTS, one of whom had subclinical hearing loss. Their heterozygous parents were clinically unaffected, but both had prolonged QT interval during a stress test (Kanovsky 2010). It has also been identified in 1/113014 European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and has been reported in ClinVar (Variation ID # 67084). In vitro functional studies and computational tools support an impact on protein function (Eckey 2014)). In addition, two other variants involving this codon (p.Arg190Gln and p.Arg190Trp) have been identified in individuals with LQTS. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant LQTS. ACMG/AMP criteria applied: PM2, PM5, PP3, PS3_Supporting, PS4_Supporting. (less)
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Pathogenic
(Nov 07, 2017)
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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: SCV000234602.10
First in ClinVar: Jul 05, 2015 Last updated: Dec 19, 2017 |
Comment:
The R190L pathogenic variant in the KCNQ1 gene has been reported multiple times in association with LQTS (Kapplinger et al., 2009; Kanovsky et al., 2010; … (more)
The R190L pathogenic variant in the KCNQ1 gene has been reported multiple times in association with LQTS (Kapplinger et al., 2009; Kanovsky et al., 2010; Andrsova et al., 2012; Crehalet et al., 2012; Wang et al., 2015). Kanovsky et al. (2010) identified the R190L variant on both KCNQ1 alleles in two siblings with severe LQTS, one of whom had sub-clinical, bilateral hearing impairment that the authors termed incomplete" Jervell Lange-Nielsen syndrome. In the same study, the heterozygous parents of these two siblings had normal QT intervals at rest, but each parent had QT prolongation during stress testing (Kanovsky et al., 2010). R190L has been reported in combination with a KCNQ1 splice variant in a young male patient with LQTS (Crehalet et al., 2012). Additionally, Wang et al. (2015) identified R190L in conjunction with variants in the MYH7, MYLK2, and TMEM70 genes among four individuals in a Chinese family with overlapping phenotypes of LQTS and hypertrophic cardiomyopathy. R190L was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, and was not observed with any significant frequency in the Exome Aggregation Consortium (ExAC) data set.The R190L variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Moreover, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Functional studies conducted by Eckey et al. (2014) demonstrated that R190L impairs phosphatidylinositol 4,5-bisphosphate (PIP2) regulation of ion channels, presumptively leading to ion channel dysfunction and LQTS phenotype. Finally, missense pathogenic variants in nearby residues, as well as in the same residue (G186S, R190W, R190Q) have been reported in the Human Gene Mutation Database in association with LQTS (Stenson et al., 2014), further supporting the functional importance of this region of the protein." (less)
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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: SCV000089226.3
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:19716085;PMID:20138589). 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:19716085;PMID:20138589). 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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Reclassification of genetic variants in children with long QT syndrome. | Westphal DS | Molecular genetics & genomic medicine | 2020 | PMID: 32383558 |
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 |
Novel Kv7.1-phosphatidylinositol 4,5-bisphosphate interaction sites uncovered by charge neutralization scanning. | Eckey K | The Journal of biological chemistry | 2014 | PMID: 24947509 |
Clinical characteristics of 30 Czech families with long QT syndrome and KCNQ1 and KCNH2 gene mutations: importance of exercise testing. | Andrsova I | Journal of electrocardiology | 2012 | PMID: 22727609 |
Patient-specific induced pluripotent stem-cell models for long-QT syndrome. | Moretti A | The New England journal of medicine | 2010 | PMID: 20660394 |
A new homozygous mutation of the KCNQ1 gene associated with both Romano-Ward and incomplete Jervell Lange-Nielsen syndromes in two sisters. | Kanovsky J | Heart rhythm | 2010 | PMID: 20138589 |
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 |
Novel mutations in KvLQT1 that affect Iks activation through interactions with Isk. | Chouabe C | Cardiovascular research | 2000 | PMID: 10728423 |
Functional effects of mutations in KvLQT1 that cause long QT syndrome. | Wang Z | Journal of cardiovascular electrophysiology | 1999 | PMID: 10376919 |
Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias. | Wang Q | Nature genetics | 1996 | PMID: 8528244 |
Text-mined citations for rs120074178 ...
HelpRecord last updated Apr 20, 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.