The TPI1 c.315G>C (p.Glu105Asp) missense variant, which is also referred to as p.Glu104Asp, is a well-known and common disease-associated variant, accounting for approximately 80% of clinical triosephosphate isomerase (TPI) deficiency. Across a selection of the available literature, the p.Glu105Asp variant was observed in 19 patients with TPI deficiency, including 13 homozygotes and six compound heterozygotes (Daar et al. 1986; Schneider et al. 1995; Arya et al. 1997; Linarello et al. 1998; Valentin et al. 2000; Yenicesu et al. 2000; Fermo et al. 2010; Sarper et al. 2013). Rodriguez-Almazan et al. (2008) demonstrated that the p.Glu105Asp variant results in instability of the TPI dimer and causes dissociation of the protein into inactive monomers, while De La Mora-De La Mora et al. (2013) showed that the p.Glu105Asp variant increases enzyme susceptibility to proteolysis. The highest allele frequency reported for this variant in the Exome Aggregation Consortium database is 0.000150 in the non-Finnish European population. Based on the collective evidence, the TPI1 p.Glu105Asp variant is classified as pathogenic for triosephosphate isomerase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
ClinVar Genomic variation as it relates to human health
NM_000365.6(TPI1):c.315G>C (p.Glu105Asp)
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.
(7)
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.
Pathogenic/Likely pathogenic
7
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000365.6(TPI1):c.315G>C (p.Glu105Asp)
Variation ID: 12468 Accession: VCV000012468.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12p13.31 12: 6869174 (GRCh38) [ NCBI UCSC ] 12: 6978338 (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 15, 2018 Aug 25, 2024 Jun 6, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000365.6:c.315G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000356.1:p.Glu105Asp missense NM_001159287.1:c.426G>C NP_001152759.1:p.Glu142Asp missense NM_001258026.2:c.69G>C NP_001244955.1:p.Glu23Asp missense NC_000012.12:g.6869174G>C NC_000012.11:g.6978338G>C NG_011948.1:g.6755G>C NG_013308.1:g.9184C>G LRG_1126:g.6755G>C LRG_1126t1:c.315G>C LRG_1126p1:p.Glu105Asp P60174:p.Glu142Asp - Protein change
- E142D, E105D, E23D
- Other names
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E104D
- Canonical SPDI
- NC_000012.12:6869173:G:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
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Exome Aggregation Consortium (ExAC) 0.00008
The Genome Aggregation Database (gnomAD), exomes 0.00008
Trans-Omics for Precision Medicine (TOPMed) 0.00011
The Genome Aggregation Database (gnomAD) 0.00012
- 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. |
|||
| TPI1 | - | - |
GRCh38 GRCh37 |
144 | 202 | |
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. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Dec 28, 2021 | RCV000013284.42 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jun 6, 2023 | RCV001851818.8 |
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
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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|---|---|---|---|---|---|
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Likely pathogenic
(Dec 28, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Triosephosphate isomerase deficiency
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
biparental
|
Genomics Facility, Ludwig-Maximilians-Universität München
Accession: SCV002073904.1
First in ClinVar: Feb 10, 2022 Last updated: Feb 10, 2022 |
Clinical Features:
Motor delay (present) , Neurodevelopmental delay (present) , Hemolytic anemia (present) , Oroticaciduria (present)
Age: 0-9 years
Sex: female
Tissue: PBMCs
Method: Agilent V6+UTR exome enrichment, Illumina NextSeq 500 sequencing
|
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Pathogenic
(May 27, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005198852.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
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Pathogenic
(Dec 17, 2018)
|
criteria provided, single submitter
Method: clinical testing
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Triosephosphate isomerase deficiency
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000914600.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The TPI1 c.315G>C (p.Glu105Asp) missense variant, which is also referred to as p.Glu104Asp, is a well-known and common disease-associated variant, accounting for approximately 80% of … (more)
The TPI1 c.315G>C (p.Glu105Asp) missense variant, which is also referred to as p.Glu104Asp, is a well-known and common disease-associated variant, accounting for approximately 80% of clinical triosephosphate isomerase (TPI) deficiency. Across a selection of the available literature, the p.Glu105Asp variant was observed in 19 patients with TPI deficiency, including 13 homozygotes and six compound heterozygotes (Daar et al. 1986; Schneider et al. 1995; Arya et al. 1997; Linarello et al. 1998; Valentin et al. 2000; Yenicesu et al. 2000; Fermo et al. 2010; Sarper et al. 2013). Rodriguez-Almazan et al. (2008) demonstrated that the p.Glu105Asp variant results in instability of the TPI dimer and causes dissociation of the protein into inactive monomers, while De La Mora-De La Mora et al. (2013) showed that the p.Glu105Asp variant increases enzyme susceptibility to proteolysis. The highest allele frequency reported for this variant in the Exome Aggregation Consortium database is 0.000150 in the non-Finnish European population. Based on the collective evidence, the TPI1 p.Glu105Asp variant is classified as pathogenic for triosephosphate isomerase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
|
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Pathogenic
(Dec 17, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Triosephosphate isomerase deficiency
(Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000967685.1
First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019 |
Comment:
The p.Glu142Asp (also known as p.Glu105Asp or p.Glu104Asp) variant in TPI1 has b een reported in at least 10 homozygous and 4 compound heterozygous individuals … (more)
The p.Glu142Asp (also known as p.Glu105Asp or p.Glu104Asp) variant in TPI1 has b een reported in at least 10 homozygous and 4 compound heterozygous individuals w ith triosephosphate isomerase deficiency (Aissa 2014, Alabdullatif 2017, Arya 19 97, Daar 1986, Nolan 2016, Pekrun 1995, Sarper 2013, Valentin 2000). It has als o been identified in 0.015% (19/129206) of European chromosomes by gnomAD (http: //gnomad.broadinstitute.org). In vitro functional studies and computational pred iction tools support an impact on protein function (Daar 1986, Ralser 2006, De L a Mora-De La Mora 2013). In summary, this variant meets criteria to be classifie d as pathogenic for autosomal recessive triosephosphate isomerase deficiency. AC MG/AMP criteria applied: PM3_VeryStrong, PS3_Moderate, PM2_Supporting, PP3. (less)
Number of individuals with the variant: 1
|
|
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Pathogenic
(Aug 17, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Triosephosphate isomerase deficiency
Affected status: unknown
Allele origin:
germline
|
Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002556914.2
First in ClinVar: Aug 08, 2022 Last updated: Dec 17, 2022 |
|
|
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Pathogenic
(Jun 06, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002240735.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TPI1 function (PMID: 17183658). An algorithm … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TPI1 function (PMID: 17183658). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 12468). This missense change has been observed in individual(s) with triosephosphate isomerase deficiency (PMID: 2876430, 10910933, 24192681). This variant is present in population databases (rs121964845, gnomAD 0.01%). This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 105 of the TPI1 protein (p.Glu105Asp). (less)
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Pathogenic
(Aug 22, 2008)
|
no assertion criteria provided
Method: literature only
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TRIOSEPHOSPHATE ISOMERASE DEFICIENCY
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000033531.6
First in ClinVar: Apr 04, 2013 Last updated: Feb 26, 2022 |
Comment on evidence:
In 2 unrelated patients with TPI deficiency (TPID; 615512), Daar et al. (1986) identified a homozygous G-to-C transversion in the TPI1 gene, resulting in a … (more)
In 2 unrelated patients with TPI deficiency (TPID; 615512), Daar et al. (1986) identified a homozygous G-to-C transversion in the TPI1 gene, resulting in a glu104-to-asp (E104D) substitution at a highly conserved residue. The E104D substitution resulted in a thermolabile enzyme. The same homozygous mutation was identified by Chang et al. (1993) in affected members of 2 Australian families with the disorder. Pekrun et al. (1995) found a homozygous E104D mutation in a 2-year-old girl, born of consanguineous Turkish parents, with severe TPI deficiency. TPI activity in red cells was reduced to about 20% of normal. Heat stability of the enzyme was strongly reduced; concentration of the physiologic substrate, DHAP, was increased 20-fold due to the metabolic block. Arya et al. (1997) found that among 7 unrelated northern European kindreds with clinical TPI deficiency, the E104D mutation accounted for 11 (79%) of 14 mutant alleles. In 3 families, molecular analysis revealed compound heterozygosity for the common E104D mutation and novel missense mutations (190450.0004 and 190450.0005). Haplotype analysis indicated a founder effect. Rodriguez-Almazan et al. (2008) determined that the E104D mutation results in instability of the TPI dimer and causes dissociation of the enzyme into inactive monomers. The substitution does not alter the catalytic residues, but it disrupts a conserved water network that spans the dimer interface and is essential for maintaining TPI dimer stability. Harris et al. (2020) identified homozygosity for the E104D mutation in the TPI1 gene in a 20-year-old woman with TPID. She was the oldest reported patient with the disorder. (less)
|
Comment:
Comment:
The p.Glu142Asp (also known as p.Glu105Asp or p.Glu104Asp) variant in TPI1 has b een reported in at least 10 homozygous and 4 compound heterozygous individuals w ith triosephosphate isomerase deficiency (Aissa 2014, Alabdullatif 2017, Arya 19 97, Daar 1986, Nolan 2016, Pekrun 1995, Sarper 2013, Valentin 2000). It has als o been identified in 0.015% (19/129206) of European chromosomes by gnomAD (http: //gnomad.broadinstitute.org). In vitro functional studies and computational pred iction tools support an impact on protein function (Daar 1986, Ralser 2006, De L a Mora-De La Mora 2013). In summary, this variant meets criteria to be classifie d as pathogenic for autosomal recessive triosephosphate isomerase deficiency. AC MG/AMP criteria applied: PM3_VeryStrong, PS3_Moderate, PM2_Supporting, PP3.
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TPI1 function (PMID: 17183658). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 12468). This missense change has been observed in individual(s) with triosephosphate isomerase deficiency (PMID: 2876430, 10910933, 24192681). This variant is present in population databases (rs121964845, gnomAD 0.01%). This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 105 of the TPI1 protein (p.Glu105Asp).
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 TPI1 c.315G>C (p.Glu105Asp) missense variant, which is also referred to as p.Glu104Asp, is a well-known and common disease-associated variant, accounting for approximately 80% of clinical triosephosphate isomerase (TPI) deficiency. Across a selection of the available literature, the p.Glu105Asp variant was observed in 19 patients with TPI deficiency, including 13 homozygotes and six compound heterozygotes (Daar et al. 1986; Schneider et al. 1995; Arya et al. 1997; Linarello et al. 1998; Valentin et al. 2000; Yenicesu et al. 2000; Fermo et al. 2010; Sarper et al. 2013). Rodriguez-Almazan et al. (2008) demonstrated that the p.Glu105Asp variant results in instability of the TPI dimer and causes dissociation of the protein into inactive monomers, while De La Mora-De La Mora et al. (2013) showed that the p.Glu105Asp variant increases enzyme susceptibility to proteolysis. The highest allele frequency reported for this variant in the Exome Aggregation Consortium database is 0.000150 in the non-Finnish European population. Based on the collective evidence, the TPI1 p.Glu105Asp variant is classified as pathogenic for triosephosphate isomerase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Comment:
The p.Glu142Asp (also known as p.Glu105Asp or p.Glu104Asp) variant in TPI1 has b een reported in at least 10 homozygous and 4 compound heterozygous individuals w ith triosephosphate isomerase deficiency (Aissa 2014, Alabdullatif 2017, Arya 19 97, Daar 1986, Nolan 2016, Pekrun 1995, Sarper 2013, Valentin 2000). It has als o been identified in 0.015% (19/129206) of European chromosomes by gnomAD (http: //gnomad.broadinstitute.org). In vitro functional studies and computational pred iction tools support an impact on protein function (Daar 1986, Ralser 2006, De L a Mora-De La Mora 2013). In summary, this variant meets criteria to be classifie d as pathogenic for autosomal recessive triosephosphate isomerase deficiency. AC MG/AMP criteria applied: PM3_VeryStrong, PS3_Moderate, PM2_Supporting, PP3.
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TPI1 function (PMID: 17183658). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 12468). This missense change has been observed in individual(s) with triosephosphate isomerase deficiency (PMID: 2876430, 10910933, 24192681). This variant is present in population databases (rs121964845, gnomAD 0.01%). This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 105 of the TPI1 protein (p.Glu105Asp).
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Child Neurology: Triosephosphate isomerase deficiency. | Harris C | Neurology | 2020 | PMID: 32873690 |
| Chromosomal microarray in a highly consanguineous population: diagnostic yield, utility of regions of homozygosity, and novel mutations. | Alabdullatif MA | Clinical genetics | 2017 | PMID: 27717089 |
| Whole Exome Sequencing in Pediatric Neurology Patients: Clinical Implications and Estimated Cost Analysis. | Nolan D | Journal of child neurology | 2016 | PMID: 26863999 |
| Hemolytic anemia and progressive neurologic impairment: think about triosephosphate isomerase deficiency. | Aissa K | Fetal and pediatric pathology | 2014 | PMID: 24840153 |
| Mild hemolytic anemia, progressive neuromotor retardation and fatal outcome: a disorder of glycolysis, triose- phosphate isomerase deficiency. | Sarper N | The Turkish journal of pediatrics | 2013 | PMID: 24192681 |
| The E104D mutation increases the susceptibility of human triosephosphate isomerase to proteolysis. Asymmetric cleavage of the two monomers of the homodimeric enzyme. | De La Mora-De La Mora I | Biochimica et biophysica acta | 2013 | PMID: 24056040 |
| Triose phosphate isomerase deficiency associated with two novel mutations in TPI gene. | Fermo E | European journal of haematology | 2010 | PMID: 20374271 |
| Structural basis of human triosephosphate isomerase deficiency: mutation E104D is related to alterations of a conserved water network at the dimer interface. | Rodríguez-Almazán C | The Journal of biological chemistry | 2008 | PMID: 18562316 |
| Triose phosphate isomerase deficiency is caused by altered dimerization--not catalytic inactivity--of the mutant enzymes. | Ralser M | PloS one | 2006 | PMID: 17183658 |
| Triosephosphate isomerase deficiency with elevated sweat chloride test: report of a case. | Yenicesu I | The Turkish journal of pediatrics | 2000 | PMID: 11196750 |
| Triose phosphate isomerase deficiency in 3 French families: two novel null alleles, a frameshift mutation (TPI Alfortville) and an alteration in the initiation codon (TPI Paris). | Valentin C | Blood | 2000 | PMID: 10910933 |
| Triosephosphate isomerase deficiency in a child with congenital hemolytic anemia and severe hypotonia. | Linarello RE | Pediatric hematology and oncology | 1998 | PMID: 9842650 |
| Evidence for founder effect of the Glu104Asp substitution and identification of new mutations in triosephosphate isomerase deficiency. | Arya R | Human mutation | 1997 | PMID: 9338582 |
| Triosephosphate isomerase deficiency: biochemical and molecular genetic analysis for prenatal diagnosis. | Pekrun A | Clinical genetics | 1995 | PMID: 7628118 |
| Triosephosphate isomerase deficiency: repetitive occurrence of point mutation in amino acid 104 in multiple apparently unrelated families. | Schneider A | American journal of hematology | 1995 | PMID: 7485100 |
| Human triosephosphate isomerase deficiency resulting from mutation of Phe-240. | Chang ML | American journal of human genetics | 1993 | PMID: 8503454 |
| Human triose-phosphate isomerase deficiency: a single amino acid substitution results in a thermolabile enzyme. | Daar IO | Proceedings of the National Academy of Sciences of the United States of America | 1986 | PMID: 2876430 |
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Text-mined citations for rs121964845 ...
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 Sep 29, 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.