ClinVar Genomic variation as it relates to human health
NM_000162.5(GCK):c.127C>T (p.Arg43Cys)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000162.5(GCK):c.127C>T (p.Arg43Cys)
Variation ID: 585911 Accession: VCV000585911.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7p13 7: 44153382 (GRCh38) [ NCBI UCSC ] 7: 44192981 (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 20, 2018 Oct 8, 2024 Aug 13, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000162.5:c.127C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000153.1:p.Arg43Cys missense NM_001354800.1:c.127C>T NP_001341729.1:p.Arg43Cys missense NM_033507.3:c.130C>T NP_277042.1:p.Arg44Cys missense NM_033508.3:c.124C>T NP_277043.1:p.Arg42Cys missense NC_000007.14:g.44153382G>A NC_000007.13:g.44192981G>A NG_008847.2:g.49789C>T LRG_1074:g.49789C>T LRG_1074t1:c.127C>T LRG_1074p1:p.Arg43Cys LRG_1074t2:c.130C>T LRG_1074p2:p.Arg44Cys - Protein change
- R43C, R44C, R42C
- Other names
- NM_000162.5(GCK):c.127C>T
- p.Arg43Cys
- Canonical SPDI
- NC_000007.14:44153381:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00002
- Links
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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GCK | - | - |
GRCh38 GRCh37 |
1089 | 1115 |
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
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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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Jan 12, 2024 | RCV000711761.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 2, 2022 | RCV002285407.3 | |
GCK-related disorder
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Pathogenic (1) |
no assertion criteria provided
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Mar 4, 2024 | RCV004751674.1 |
Pathogenic (2) |
reviewed by expert panel
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Aug 13, 2023 | RCV003325972.3 |
Submissions - Germline
Classification
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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
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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
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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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Pathogenic
(Aug 13, 2023)
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reviewed by expert panel
Method: curation
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Monogenic diabetes
(Semidominant inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen Monogenic Diabetes Variant Curation Expert Panel
FDA Recognized Database
Accession: SCV004032096.1 First in ClinVar: Sep 09, 2023 Last updated: Sep 09, 2023 |
Comment:
The c.127C>T variant in the glucokinase gene, GCK, causes an amino acid change of arginine to cysteine at codon 43 (p.(Arg43Cys)) of NM_000162.5. GCK is … (more)
The c.127C>T variant in the glucokinase gene, GCK, causes an amino acid change of arginine to cysteine at codon 43 (p.(Arg43Cys)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.924, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Additionally, established functional studies demonstrated the p.Arg43Cys protein has a relative activity index (RAI) < 0.5, indicating that this variant impacts protein function (PS3_Moderate; PMID: 25015100). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in at least eight unrelated individuals with hyperglycemia/diabetes (PS4; PMIDs: 30592380, 21348868, PMID 23771172, 25015100). One of these individuals was homozygous for c.127C>T and had permanent neonatal diabetes mellitus (PNDM) and negative testing for ABCC8, KCNJ11, INS and EIF2AK3 (PP4; PMID 25015100). This variant also segregated with diabetes/hyperglycemia, with 5 informative meioses in one family (PP1_Strong; PMID 21348868). Another missense variant, c.128G>A (p.Arg43His), has been interpreted as pathogenic by the ClinGen MDEP and p.Arg43Cys has a greater Grantham distance (PM5). Taken together, this evidence supports the classification of this variant as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP1_Strong, PS4, PM5, PP2, PP3, PP4, PM2_Supporting, PS3_Moderate. (less)
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Pathogenic
(May 11, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics
Accession: SCV000842155.2
First in ClinVar: Oct 20, 2018 Last updated: Jan 26, 2021 |
Comment:
Not found in the total gnomAD dataset, and the data is high quality. Predicted to have a damaging effect on the protein. Other pathogenic or … (more)
Not found in the total gnomAD dataset, and the data is high quality. Predicted to have a damaging effect on the protein. Other pathogenic or likely pathogenic variants affect the same amino acid. Found in multiple individuals with expected phenotype for this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. Segregation with disease in affected individuals from a single family. (less)
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Pathogenic
(Aug 02, 2022)
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criteria provided, single submitter
Method: research
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Maturity-onset diabetes of the young type 2
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Geisinger Clinic, Geisinger Health System
Accession: SCV002562156.1
First in ClinVar: Oct 01, 2022 Last updated: Oct 01, 2022 |
Comment:
PS4, PP1_Strong, PP2, PP3, PP4, PM2, PS3_Moderate, PM5
Number of individuals with the variant: 2
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Pathogenic
(Jan 12, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV004295191.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 43 of the GCK protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 43 of the GCK protein (p.Arg43Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with maturity onset diabetes of the young (PMID: 19790256, 30592380). ClinVar contains an entry for this variant (Variation ID: 585911). 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 not expected to disrupt GCK protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects GCK function (PMID: 30592380). This variant disrupts the p.Arg43 amino acid residue in GCK. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11942313, 22493702, 22611063, 28726111, 30155490, 30245511, 31638168, 33046911, 34108472; Invitae). 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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Pathogenic
(Jul 13, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV004565214.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
Comment:
The GCK c c.127C>T; p.Arg43Cys variant (rs1486280029) is reported in the literature in multiple individuals and families affected with MODY and neonatal diabetes (Ellard 2013, … (more)
The GCK c c.127C>T; p.Arg43Cys variant (rs1486280029) is reported in the literature in multiple individuals and families affected with MODY and neonatal diabetes (Ellard 2013, Marucci 2023, Osbak 2009, Wang 2019). This variant is also reported in ClinVar (Variation ID: 585911). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Additionally, other amino acid substitutions at this codon (Gly, Ser, His, Pro) have been reported in individuals with MODY with most of them demonstrating pathogenicity (Osbak 2009). Computational analyses predict that this variant is neutral (REVEL: 0.924). Based on available information, this variant is considered to be pathogenic. References: Ellard S et al. Improved genetic testing for monogenic diabetes using targeted next-generation sequencing. Diabetologia. 2013 Sep;56(9):1958-63. PMID: 23771172. Marucci A et al. MODY patients carrying mutation in syndromic diabetes genes. An Italian single-center experience. Acta Diabetol. 2023 Jan;60(1):131-135. PMID: 36227502. Osbak KK et al. Update on mutations in glucokinase (GCK), which cause maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemic hypoglycemia. Hum Mutat. 2009 Nov;30(11):1512-26. PMID: 19790256. Wang Z et al. Identification and functional analysis of GCK gene mutations in 12 Chinese families with hyperglycemia. J Diabetes Investig. 2019 Jul;10(4):963-971. PMID: 30592380. (less)
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Pathogenic
(Feb 21, 2024)
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criteria provided, single submitter
Method: clinical testing
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Monogenic diabetes
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004813475.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Comment:
Variant summary: GCK c.127C>T (p.Arg43Cys) results in a non-conservative amino acid change located in the Hexokinase, N-terminal domain (IPR022672) of the encoded protein sequence. Five … (more)
Variant summary: GCK c.127C>T (p.Arg43Cys) results in a non-conservative amino acid change located in the Hexokinase, N-terminal domain (IPR022672) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251444 control chromosomes. c.127C>T has been reported in the literature in multiple heterozygous individuals affected with Monogenic Diabetes (e.g. Boroweic_2012, Wang_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, showing decreased catalytic activity in vitro (e.g. Wang_2019). The most pronounced variant effect results in 30%-50% of normal activity. The following publications have been ascertained in the context of this evaluation (PMID: 21348868, 30592380). ClinVar contains an entry for this variant (Variation ID: 585911). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Mar 04, 2024)
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no assertion criteria provided
Method: clinical testing
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GCK-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV005341337.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The GCK c.127C>T variant is predicted to result in the amino acid substitution p.Arg43Cys. This variant has been reported in heterozygous state in multiple individuals … (more)
The GCK c.127C>T variant is predicted to result in the amino acid substitution p.Arg43Cys. This variant has been reported in heterozygous state in multiple individuals with mature onset diabetes of the young (MODY) (Table S1, Osbak et al. 2009. PubMed ID: 19790256; Wang et al. 2019. PubMed ID: 30592380) and in one family was reported to segregate with MODY (Borowiec et al. 2012. PubMed ID: 21348868). Additionally, this variant has been reported in the homozygous state in individuals with neonatal diabetes (Raimondo et al. 2014. PubMed ID: 25015100). In vitro functional studies found this variant results in decreased catalytic activity and decrease stability at higher temperatures (Wang et al. 2019. PubMed ID: 30592380). Alternate missense variants affecting the same amino acid (p.Arg43Ser, p.Arg43Gly, p.Arg43His, p.Arg43Pro) have been reported as pathogenic (Table S1, Osbak et al. 2009. PubMed ID: 19790256). This variant has not been reported in a large population database and has been interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/585911/). This variant is interpreted as pathogenic. (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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Reduced penetrance of MODY-associated HNF1A/HNF4A variants but not GCK variants in clinically unselected cohorts. | Mirshahi UL | American journal of human genetics | 2022 | PMID: 36257325 |
Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes. | Goodrich JK | Nature communications | 2021 | PMID: 34108472 |
Pathogenic variants in actionable MODY genes are associated with type 2 diabetes. | Bonnefond A | Nature metabolism | 2020 | PMID: 33046911 |
Whole‑exome sequencing in Russian children with non‑type 1 diabetes mellitus reveals a wide spectrum of genetic variants in MODY‑related and unrelated genes. | Glotov OS | Molecular medicine reports | 2019 | PMID: 31638168 |
Identification and functional analysis of GCK gene mutations in 12 Chinese families with hyperglycemia. | Wang Z | Journal of diabetes investigation | 2019 | PMID: 30592380 |
A new clinical screening strategy and prevalence estimation for glucokinase variant-induced diabetes in an adult Chinese population. | Ma Y | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 30245511 |
Lower Circulating miR-122 Level in Patients with HNF1A Variant-Induced Diabetes Compared with Type 2 Diabetes. | Huang X | Journal of diabetes research | 2018 | PMID: 30155490 |
Glucokinase mutations in pediatric patients with impaired fasting glucose. | Aloi C | Acta diabetologica | 2017 | PMID: 28726111 |
Phenotypic severity of homozygous GCK mutations causing neonatal or childhood-onset diabetes is primarily mediated through effects on protein stability. | Raimondo A | Human molecular genetics | 2014 | PMID: 25015100 |
Less but better: cardioprotective lipid profile of patients with GCK-MODY despite lower HDL cholesterol level. | Fendler W | Acta diabetologica | 2014 | PMID: 24549415 |
Improved genetic testing for monogenic diabetes using targeted next-generation sequencing. | Ellard S | Diabetologia | 2013 | PMID: 23771172 |
Insights into the pathogenicity of rare missense GCK variants from the identification and functional characterization of compound heterozygous and double mutations inherited in cis. | Beer NL | Diabetes care | 2012 | PMID: 22611063 |
Identification and functional characterisation of novel glucokinase mutations causing maturity-onset diabetes of the young in Slovakia. | Valentínová L | PloS one | 2012 | PMID: 22493702 |
Novel glucokinase mutations in patients with monogenic diabetes - clinical outline of GCK-MD and potential for founder effect in Slavic population. | Borowiec M | Clinical genetics | 2012 | PMID: 21348868 |
HDL cholesterol as a diagnostic tool for clinical differentiation of GCK-MODY from HNF1A-MODY and type 1 diabetes in children and young adults. | Fendler W | Clinical endocrinology | 2011 | PMID: 21521320 |
Update on mutations in glucokinase (GCK), which cause maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemic hypoglycemia. | Osbak KK | Human mutation | 2009 | PMID: 19790256 |
To: Lindner T, Cockburn BN, Bell GI (1999). Molecular genetics of MODY in Germany. Diabetologia 42: 121-123. | Ziemssen F | Diabetologia | 2002 | PMID: 11942313 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/8eefadd2-11eb-46d6-88b2-35a21909f993 | - | - | - | - |
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Text-mined citations for rs1486280029 ...
HelpRecord last updated Oct 08, 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.