ClinVar Genomic variation as it relates to human health
NM_000238.4(KCNH2):c.2959_2960del (p.Leu987fs)
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_000238.4(KCNH2):c.2959_2960del (p.Leu987fs)
Variation ID: 200693 Accession: VCV000200693.31
- Type and length
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Deletion, 2 bp
- Location
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Cytogenetic: 7q36.1 7: 150947611-150947612 (GRCh38) [ NCBI UCSC ] 7: 150644699-150644700 (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 Jan 7, 2017 Apr 15, 2024 Dec 1, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000238.4:c.2959_2960del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000229.1:p.Leu987fs frameshift NM_000238.2:c.2959_2960del NM_000238.3:c.2959_2960delCT NM_172057.3:c.1939_1940del NP_742054.1:p.Leu647fs frameshift NC_000007.14:g.150947611_150947612del NC_000007.13:g.150644699_150644700del NG_008916.1:g.35315_35316del LRG_288:g.35315_35316del LRG_288t1:c.2959_2960del LRG_288p1:p.Leu987fs - Protein change
- L987fs, L647fs
- Other names
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- Canonical SPDI
- NC_000007.14:150947610:AG:
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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
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00000
Trans-Omics for Precision Medicine (TOPMed) 0.00000
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
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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KCNH2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3048 | 3130 |
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
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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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Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Dec 1, 2022 | RCV000182004.21 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jun 18, 2018 | RCV000254145.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 23, 2022 | RCV000471453.18 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 19, 2018 | RCV001842852.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 2, 2022 | RCV002470798.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 30, 2021 | RCV003227698.8 |
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
(Jan 30, 2017)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000696029.1
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
Comment:
Variant summary: The KCNH2 c.2959_2960delCT (p.Leu987Valfs) variant results in a premature termination codon, predicted to cause a truncated or absent KCNH2 protein due to nonsense … (more)
Variant summary: The KCNH2 c.2959_2960delCT (p.Leu987Valfs) variant results in a premature termination codon, predicted to cause a truncated or absent KCNH2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant was found in 2/98624 control chromosomes at a frequency of 0.0000203, which does not exceed the estimated maximal expected allele frequency of a pathogenic KCNH2 variant (0.0001233). Multiple publications have cited the variant in affected individuals diagnosed with LQTS. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
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Pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001446721.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Wolff-Parkinson-White pattern (present) , Prolonged QTc interval (present)
Sex: female
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Pathogenic
(Nov 19, 2018)
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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: SCV001350152.2
First in ClinVar: Jun 22, 2020 Last updated: Jan 12, 2022 |
Comment:
This variant (also known as p.P986fs+130X in the literature) resuolts in the deletion of 2 nucleotides in exon 12 of the KCNH2 gene, creating a … (more)
This variant (also known as p.P986fs+130X in the literature) resuolts in the deletion of 2 nucleotides in exon 12 of the KCNH2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in multiple individuals from three families affected with long QT syndrome (PMID: 10973849, 26669661) and in individuals referred for long QT testing (PMID: 19716085, 23098067). This variant has been identified in 1/241050 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of KCNH2 function is a known mechanism of disease. Based on available evidence, this variant is classified as Pathogenic. (less)
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Pathogenic
(Jun 18, 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: SCV000320148.6
First in ClinVar: Oct 02, 2016 Last updated: Nov 29, 2022 |
Comment:
The c.2959_2960delCT pathogenic mutation, located in coding exon 12 of the KCNH2 gene, results from a deletion of two nucleotides between positions 2959 and 2960, … (more)
The c.2959_2960delCT pathogenic mutation, located in coding exon 12 of the KCNH2 gene, results from a deletion of two nucleotides between positions 2959 and 2960, causing a translational frameshift with a predicted alternate stop codon (p.L987Vfs*131). This alteration was first reported in a family with Romano-Ward syndrome (Splawski I et al. Circulation. 2000;102(10):1178-85 (reported as P986fs/130). This alteration has also been detected in cohorts submitted for long QT syndrome genetic testing (Kapplinger JD et al. Heart Rhythm. 2009;6(9):1297-303; Stattin EL et al. BMC Cardiovasc Disord. 2012;12:95; Du Pre BC et al. Front Physiol, 2017 Aug;8:590). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(Sep 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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Long QT syndrome 2
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002769463.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with long QT syndrome 2 (MIM#613688). Gain of function is also a known mechanism associated with short QT syndrome 1 (MIM#609620) (OMIM, PMIDs: 10753933, 21777565). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 20301308). (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0701 - Other premature termination variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Many frameshift variants downstream have been reported as likely pathogenic/pathogenic (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple unrelated individuals with long QT syndrome, and as likely pathogenic/pathogenic (PMID: 32893267, ClinVar). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Jul 12, 2021)
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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: SCV000234307.10
First in ClinVar: Jul 05, 2015 Last updated: Mar 04, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (Lek et al., 2016); Frameshift variant predicted to result in protein truncation in a gene for … (more)
Not observed at significant frequency in large population cohorts (Lek et al., 2016); Frameshift variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Reported in ClinVar as pathogenic (ClinVar Variant ID# 200693; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 27535533, 23098067, 19841300, 19165230, 28861002, 19716085, 10973849, 26669661, 21737021) (less)
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Pathogenic
(Mar 30, 2021)
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criteria provided, single submitter
Method: clinical testing
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Short QT syndrome type 1
Long QT syndrome 2
Affected status: unknown
Allele origin:
germline
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Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Accession: SCV003924214.1
First in ClinVar: May 20, 2023 Last updated: May 20, 2023 |
Comment:
KCNH2 NM_000238.3 exon 12 p.Leu987Valfs*131 (c.2959_2960del): This variant has been reported in the literature in at least 6 individuals with a clinical suspicion or diagnosis … (more)
KCNH2 NM_000238.3 exon 12 p.Leu987Valfs*131 (c.2959_2960del): This variant has been reported in the literature in at least 6 individuals with a clinical suspicion or diagnosis of Long QT syndrome (also reported as P986fs; Splawski 2000 PMID:10973849, Kapplinger 2009 PMID:19716085, Stattin 2012 PMID:23098067, Itoh 2016 PMID:26669661). This variant is present in 0.0009% (1/110530) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/7-150644698-CAG-C). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:200693). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant is a deletion of 2 nucleotides beginning at position 2959 and creates a premature stop codon 131 amino acids downstream from this location which results in an absent or abnormal protein. Loss of function variants are a known mechanism of disease for this gene (Hedley 2009 PMID:19862833). In summary, this variant is classified as pathogenic. (less)
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Pathogenic
(Aug 23, 2022)
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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: SCV000543466.9
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Leu987Valfs*131) in the KCNH2 gene. It … (more)
For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Leu987Valfs*131) in the KCNH2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KCNH2 are known to be pathogenic (PMID: 10973849, 19862833). This variant is present in population databases (rs748706373, gnomAD 0.0009%). This premature translational stop signal has been observed in individuals with long QT syndrome (PMID: 10973849, 19716085, 23098067, 26669661). This variant is also known as p.P986fs/130. ClinVar contains an entry for this variant (Variation ID: 200693). (less)
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Pathogenic
(Dec 01, 2022)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV002821859.8
First in ClinVar: Jan 21, 2023 Last updated: Apr 15, 2024 |
Comment:
KCNH2: PVS1, PM2, PS4:Moderate
Number of individuals with the variant: 1
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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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Long QT Syndrome Overview. | Adam MP | - | 2024 | PMID: 20301308 |
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 |
Analysis of 24-h Rhythm in Ventricular Repolarization Identifies QT Diurnality As a Novel Clinical Parameter Associated with Previous Ventricular Arrhythmias in Heart Failure Patients. | Du Pre BC | Frontiers in physiology | 2017 | PMID: 28861002 |
The genetics underlying acquired long QT syndrome: impact for genetic screening. | Itoh H | European heart journal | 2016 | PMID: 26715165 |
Asymmetry of parental origin in long QT syndrome: preferential maternal transmission of KCNQ1 variants linked to channel dysfunction. | Itoh H | European journal of human genetics : EJHG | 2016 | PMID: 26669661 |
Founder mutations characterise the mutation panorama in 200 Swedish index cases referred for Long QT syndrome genetic testing. | Stattin EL | BMC cardiovascular disorders | 2012 | PMID: 23098067 |
The hERG K(+) channel S4 domain L532P mutation: characterization at 37°C. | Zhang YH | Biochimica et biophysica acta | 2011 | PMID: 21777565 |
The genetic basis of long QT and short QT syndromes: a mutation update. | Hedley PL | Human mutation | 2009 | PMID: 19862833 |
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 |
Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. | Splawski I | Circulation | 2000 | PMID: 10973849 |
The dominant negative LQT2 mutation A561V reduces wild-type HERG expression. | Kagan A | The Journal of biological chemistry | 2000 | PMID: 10753933 |
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Text-mined citations for rs748706373 ...
HelpRecord last updated Apr 15, 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.