The p.G661S variant (also known as c.1981G>A), located in coding exon 12 of the NOTCH1 gene, results from a G to A substitution at nucleotide position 1981. The glycine at codon 661 is replaced by serine, an amino acid with similar properties. Among patients in a cohort with left ventricular outflow tract malformations, this variant was reported in four patients who exhibited bicuspid aortic valve, aortic valve stenosis, coarctation of the aorta, or hypoplastic left heart syndrome, and in all four cases, this variant also was described in an unaffected parent (McBride KL et al, Hum. Mol. Genet. 2008;17(18):2886-93). In the same study, this variant was reported in 1/212 healthy control subjects. Further in vitro functional analysis of this variant demonstrated only slight or no difference compared to wild-type, in surface protein, ligand-activated signaling, trafficking or folding (McBride KL et al, Hum. Mol. Genet. 2008;17(18):2886-93; Riley MF et al. Biochim Biophys Acta. 2011;1812(1):121-9). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
ClinVar Genomic variation as it relates to human health
NM_017617.5(NOTCH1):c.1981G>A (p.Gly661Ser)
Germline
Classification
Help
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.
(10)
Help
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.
Conflicting classifications of pathogenicity
Uncertain significance(3); Likely benign(2)
Uncertain significance(3); Likely benign(2)
10
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_017617.5(NOTCH1):c.1981G>A (p.Gly661Ser)
Variation ID: 264541 Accession: VCV000264541.68
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 9q34.3 9: 136515323 (GRCh38) [ NCBI UCSC ] 9: 139409775 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Dec 19, 2017 Oct 8, 2024 Sep 16, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_017617.5:c.1981G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_060087.3:p.Gly661Ser missense NC_000009.12:g.136515323C>T NC_000009.11:g.139409775C>T NG_007458.1:g.35464G>A LRG_1122:g.35464G>A LRG_1122t1:c.1981G>A LRG_1122p1:p.Gly661Ser - Protein change
- G661S
- Other names
-
p.Gly661Ser
- Canonical SPDI
- NC_000009.12:136515322:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
-
0.00040 (T)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
1000 Genomes Project 0.00040
1000 Genomes Project 30x 0.00047
The Genome Aggregation Database (gnomAD) 0.00034
Trans-Omics for Precision Medicine (TOPMed) 0.00037
Exome Aggregation Consortium (ExAC) 0.00038
The Genome Aggregation Database (gnomAD), exomes 0.00038
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00039
- Links
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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
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. |
|||
| NOTCH1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3494 | 3765 | |
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. |
|---|---|---|---|---|
| Uncertain significance (5) |
criteria provided, multiple submitters, no conflicts
|
Sep 16, 2024 | RCV000519623.21 | |
| Likely benign (1) |
criteria provided, single submitter
|
Jan 24, 2024 | RCV000555279.21 | |
| not provided (1) |
no classification provided
|
- | RCV001535730.10 | |
| Likely benign (1) |
no assertion criteria provided
|
Sep 26, 2022 | RCV002285156.8 | |
| Likely benign (1) |
criteria provided, single submitter
|
Feb 2, 2022 | RCV002272196.9 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Dec 15, 2023 | RCV002311210.9 |
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. |
|
|---|---|---|---|---|---|
|
Likely benign
(Jan 24, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Adams-Oliver syndrome 5
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000659386.9
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
|
|
|
Uncertain significance
(Dec 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial thoracic aortic aneurysm and aortic dissection
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000320542.7
First in ClinVar: Oct 03, 2016 Last updated: May 01, 2024 |
Comment:
The p.G661S variant (also known as c.1981G>A), located in coding exon 12 of the NOTCH1 gene, results from a G to A substitution at nucleotide … (more)
The p.G661S variant (also known as c.1981G>A), located in coding exon 12 of the NOTCH1 gene, results from a G to A substitution at nucleotide position 1981. The glycine at codon 661 is replaced by serine, an amino acid with similar properties. Among patients in a cohort with left ventricular outflow tract malformations, this variant was reported in four patients who exhibited bicuspid aortic valve, aortic valve stenosis, coarctation of the aorta, or hypoplastic left heart syndrome, and in all four cases, this variant also was described in an unaffected parent (McBride KL et al, Hum. Mol. Genet. 2008;17(18):2886-93). In the same study, this variant was reported in 1/212 healthy control subjects. Further in vitro functional analysis of this variant demonstrated only slight or no difference compared to wild-type, in surface protein, ligand-activated signaling, trafficking or folding (McBride KL et al, Hum. Mol. Genet. 2008;17(18):2886-93; Riley MF et al. Biochim Biophys Acta. 2011;1812(1):121-9). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. (less)
|
|
|
Uncertain significance
(Sep 16, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000617311.8
First in ClinVar: Dec 19, 2017 Last updated: Oct 08, 2024 |
Comment:
Published functional studies suggest that this variant is associated with reduced ligand-induced Notch1 signaling, possibly due to reduced cell surface expression; however, a specific mechanism … (more)
Published functional studies suggest that this variant is associated with reduced ligand-induced Notch1 signaling, possibly due to reduced cell surface expression; however, a specific mechanism was not established and it is not known whether the experimental conditions represent the physiologic effect of the variant in vivo (PMID: 20951801, 18593716); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 20981092, 26164125, 21563298, 18593716, 32165302, 36599283, 30582441, 20951801, 29641532) (less)
|
|
|
Likely benign
(Feb 02, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Aortic valve disease 1
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002557881.1
First in ClinVar: Aug 08, 2022 Last updated: Aug 08, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely benign. Following criteria are met: 0102 - Loss of function is a known … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely benign. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Adams-Oliver syndrome 5 (MIM#616028) and aortic valve disease 1 (MIM#109730). A gain of function mechanism has also been described, but this is more in association with cancer (OMIM, PMID: 30582441). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 30582441). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to serine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (101 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated EGF-like domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported multiple times as a VUS, and has been observed in at least four individuals with congenital cardiovascular malformations but also within a control cohort (ClinVar, PMID: 18593716). (I) 1010 - Functional evidence for this variant is inconclusive. Transfected NIH3T3 cells demonstrated similar luciferase activity and protein expression to wildtype cells, but a significant decrease in ligand induction. It is unclear if this reduction is enough to induce disease in an in vivo setting (PMID: 18593716). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
|
|
|
Uncertain significance
(Jul 06, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004225191.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
BS1, PP2, PS4_moderate
Number of individuals with the variant: 13
|
|
|
Uncertain significance
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001930623.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
|
|
|
Uncertain significance
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
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: SCV001955759.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
|
Uncertain significance
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
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: SCV001965096.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
|
|
|
Likely benign
(Sep 26, 2022)
|
no assertion criteria provided
Method: clinical testing
|
Pulmonary arterial hypertension
Affected status: unknown
Allele origin:
germline
|
John Welsh Cardiovascular Diagnostic Laboratory, Baylor College of Medicine
Accession: SCV002575041.1
First in ClinVar: Oct 01, 2022 Last updated: Oct 01, 2022 |
|
|
|
not provided
(-)
|
no classification provided
Method: phenotyping only
|
Aortic valve disorder
Adams-Oliver syndrome 2
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
unknown
|
GenomeConnect - Invitae Patient Insights Network
Accession: SCV001749832.2
First in ClinVar: Jul 18, 2021 Last updated: Jun 17, 2024 |
Comment:
Variant interpreted as Uncertain significance and reported on 10-28-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided … (more)
Variant interpreted as Uncertain significance and reported on 10-28-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less)
Clinical Features:
Vertigo (present) , Ear malformation (present) , Hyperextensible skin (present) , Hypopigmentation of the skin (present) , Abnormal cardiovascular system morphology (present) , Abnormal pattern … (more)
Vertigo (present) , Ear malformation (present) , Hyperextensible skin (present) , Hypopigmentation of the skin (present) , Abnormal cardiovascular system morphology (present) , Abnormal pattern of respiration (present) , Abnormal intestine morphology (present) , Abnormal stomach morphology (present) , Abnormal muscle physiology (present) , Abnormality of the musculature of the limbs (present) , Abnormal curvature of the vertebral column (present) , Increased susceptibility to fractures (present) , Abnormality of coordination (present) , Generalized hypotonia (present) , Memory impairment (present) , Movement disorder (present) , Abnormal aggressive, impulsive or violent behavior (present) , Anxiety (present) , Motor stereotypies (present) , Maternal teratogenic exposure (present) (less)
Indication for testing: Diagnostic
Age: 30-39 years
Sex: male
Testing laboratory: Invitae
Date variant was reported to submitter: 2019-10-28
Testing laboratory interpretation: Uncertain significance
|
Comment:
Comment:
Published functional studies suggest that this variant is associated with reduced ligand-induced Notch1 signaling, possibly due to reduced cell surface expression; however, a specific mechanism was not established and it is not known whether the experimental conditions represent the physiologic effect of the variant in vivo (PMID: 20951801, 18593716); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 20981092, 26164125, 21563298, 18593716, 32165302, 36599283, 30582441, 20951801, 29641532)
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely benign. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Adams-Oliver syndrome 5 (MIM#616028) and aortic valve disease 1 (MIM#109730). A gain of function mechanism has also been described, but this is more in association with cancer (OMIM, PMID: 30582441). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 30582441). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to serine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (101 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated EGF-like domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported multiple times as a VUS, and has been observed in at least four individuals with congenital cardiovascular malformations but also within a control cohort (ClinVar, PMID: 18593716). (I) 1010 - Functional evidence for this variant is inconclusive. Transfected NIH3T3 cells demonstrated similar luciferase activity and protein expression to wildtype cells, but a significant decrease in ligand induction. It is unclear if this reduction is enough to induce disease in an in vivo setting (PMID: 18593716). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
BS1, PP2, PS4_moderate
Comment:
Variant interpreted as Uncertain significance and reported on 10-28-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
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. |
Comment:
The p.G661S variant (also known as c.1981G>A), located in coding exon 12 of the NOTCH1 gene, results from a G to A substitution at nucleotide position 1981. The glycine at codon 661 is replaced by serine, an amino acid with similar properties. Among patients in a cohort with left ventricular outflow tract malformations, this variant was reported in four patients who exhibited bicuspid aortic valve, aortic valve stenosis, coarctation of the aorta, or hypoplastic left heart syndrome, and in all four cases, this variant also was described in an unaffected parent (McBride KL et al, Hum. Mol. Genet. 2008;17(18):2886-93). In the same study, this variant was reported in 1/212 healthy control subjects. Further in vitro functional analysis of this variant demonstrated only slight or no difference compared to wild-type, in surface protein, ligand-activated signaling, trafficking or folding (McBride KL et al, Hum. Mol. Genet. 2008;17(18):2886-93; Riley MF et al. Biochim Biophys Acta. 2011;1812(1):121-9). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Comment:
Published functional studies suggest that this variant is associated with reduced ligand-induced Notch1 signaling, possibly due to reduced cell surface expression; however, a specific mechanism was not established and it is not known whether the experimental conditions represent the physiologic effect of the variant in vivo (PMID: 20951801, 18593716); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 20981092, 26164125, 21563298, 18593716, 32165302, 36599283, 30582441, 20951801, 29641532)
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely benign. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Adams-Oliver syndrome 5 (MIM#616028) and aortic valve disease 1 (MIM#109730). A gain of function mechanism has also been described, but this is more in association with cancer (OMIM, PMID: 30582441). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 30582441). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to serine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (101 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated EGF-like domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported multiple times as a VUS, and has been observed in at least four individuals with congenital cardiovascular malformations but also within a control cohort (ClinVar, PMID: 18593716). (I) 1010 - Functional evidence for this variant is inconclusive. Transfected NIH3T3 cells demonstrated similar luciferase activity and protein expression to wildtype cells, but a significant decrease in ligand induction. It is unclear if this reduction is enough to induce disease in an in vivo setting (PMID: 18593716). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
BS1, PP2, PS4_moderate
Comment:
Variant interpreted as Uncertain significance and reported on 10-28-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Whole Exome Sequencing Reveals the Major Genetic Contributors to Nonsyndromic Tetralogy of Fallot. | Page DJ | Circulation research | 2019 | PMID: 30582441 |
| Germline mutations in candidate predisposition genes in individuals with cutaneous melanoma and at least two independent additional primary cancers. | Pritchard AL | PloS one | 2018 | PMID: 29641532 |
| NOTCH1 missense alleles associated with left ventricular outflow tract defects exhibit impaired receptor processing and defective EMT. | Riley MF | Biochimica et biophysica acta | 2011 | PMID: 20951801 |
| A map of human genome variation from population-scale sequencing. | 1000 Genomes Project Consortium | Nature | 2010 | PMID: 20981092 |
| NOTCH1 mutations in individuals with left ventricular outflow tract malformations reduce ligand-induced signaling. | McBride KL | Human molecular genetics | 2008 | PMID: 18593716 |
Text-mined citations for rs201077220 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 25, 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.