ClinVar Genomic variation as it relates to human health
NM_006363.6(SEC23B):c.1385A>G (p.Tyr462Cys)
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.
Likely pathogenic(3); Uncertain significance(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_006363.6(SEC23B):c.1385A>G (p.Tyr462Cys)
Variation ID: 1325043 Accession: VCV001325043.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 20p11.23 20: 18535723 (GRCh38) [ NCBI UCSC ] 20: 18516367 (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 Nov 29, 2021 Apr 15, 2024 Jan 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_006363.6:c.1385A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_006354.2:p.Tyr462Cys missense NM_001172745.3:c.1385A>G NP_001166216.1:p.Tyr462Cys missense NM_001172746.3:c.1331A>G NP_001166217.1:p.Tyr444Cys missense NM_006363.4:c.[1385A>G] NM_032985.6:c.1385A>G NP_116780.1:p.Tyr462Cys missense NM_032986.5:c.1385A>G NP_116781.1:p.Tyr462Cys missense NC_000020.11:g.18535723A>G NC_000020.10:g.18516367A>G NG_016281.2:g.33242A>G LRG_1134:g.33242A>G LRG_1134t1:c.1385A>G LRG_1134p1:p.Tyr462Cys - Protein change
- Y444C, Y462C
- Other names
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- Canonical SPDI
- NC_000020.11:18535722:A:G
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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) 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00003
Exome Aggregation Consortium (ExAC) 0.00004
- 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
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. |
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SEC23B | - | - |
GRCh38 GRCh37 |
565 | 678 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
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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Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Oct 1, 2023 | RCV001783720.9 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Mar 22, 2022 | RCV001823309.5 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 29, 2024 | RCV003772156.1 |
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
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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
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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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Likely pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Congenital dyserythropoietic anemia, type II
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV002073072.1
First in ClinVar: Feb 04, 2022 Last updated: Feb 04, 2022 |
Comment:
The missense variant p.Y462C in SEC23B (NM_006363.6) has previously been reported in patients in homozygous state affected with congenital dyserythropoietic anemia type II (Prasanth et … (more)
The missense variant p.Y462C in SEC23B (NM_006363.6) has previously been reported in patients in homozygous state affected with congenital dyserythropoietic anemia type II (Prasanth et al). There is a large physicochemical difference between tyrosine and cysteine, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. The p.Y462C missense variant is predicted to be damaging by both SIFT and PolyPhen2. The tyrosine residue at codon 462 of SEC23B is conserved in all mammalian species. The nucleotide c.1385 in SEC23B is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. (less)
Clinical Features:
Congenital hypoplastic anemia (present) , Splenomegaly (present)
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Uncertain significance
(Mar 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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Congenital dyserythropoietic anemia, type II
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002318852.1
First in ClinVar: Apr 02, 2022 Last updated: Apr 02, 2022 |
Comment:
Same or different nucleotide change resulting in same amino acid change has been previously reported to be associated with SEC23B related disorder ( PMID:19561605). The … (more)
Same or different nucleotide change resulting in same amino acid change has been previously reported to be associated with SEC23B related disorder ( PMID:19561605). The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000278 ). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.81>=0.6, 3CNET: 0.831>=0.75). Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Anemia (present) , Hepatosplenomegaly (present) , Jaundice (present)
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Likely pathogenic
(Oct 09, 2021)
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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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Revvity Omics, Revvity
Accession: SCV002019159.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Likely pathogenic
(Jan 29, 2024)
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criteria provided, single submitter
Method: clinical testing
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Congenital dyserythropoietic anemia, type II
Cowden syndrome 7
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:
germline
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Invitae
Accession: SCV004571386.1
First in ClinVar: Feb 28, 2024 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 462 of the SEC23B protein … (more)
This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 462 of the SEC23B protein (p.Tyr462Cys). This variant is present in population databases (rs780978419, gnomAD 0.02%). This missense change has been observed in individuals with congenital dyserythropoietic anemia type II (PMID: 19561605, 24801240, 25044164, 25418799, 28879554). ClinVar contains an entry for this variant (Variation ID: 1325043). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SEC23B protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
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Uncertain significance
(Oct 01, 2023)
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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: SCV004149920.4
First in ClinVar: Nov 20, 2023 Last updated: Apr 15, 2024 |
Comment:
SEC23B: PM2, PP3
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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Congenital dyserythropoietic anemia type II mimicking hereditary spherocytosis in Indian patient with SEC23B-Y462C mutations. | Kedar P | Annals of hematology | 2017 | PMID: 28879554 |
Homozygosity mapping reveals founder SEC23B-Y462C mutations in Indian congenital dyserythropoietic anemia type II. | Singleton B | Clinical genetics | 2015 | PMID: 25418799 |
Congenital dyserythropoietic anemia, type II with SEC23B exon 12 c.1385 A → G mutation, and pseudo-Gaucher cells in two siblings. | Sharma P | Hematology (Amsterdam, Netherlands) | 2015 | PMID: 24801240 |
Retrospective cohort study of 205 cases with congenital dyserythropoietic anemia type II: definition of clinical and molecular spectrum and identification of new diagnostic scores. | Russo R | American journal of hematology | 2014 | PMID: 25044164 |
Mutations affecting the secretory COPII coat component SEC23B cause congenital dyserythropoietic anemia type II. | Schwarz K | Nature genetics | 2009 | PMID: 19561605 |
Text-mined citations for rs780978419 ...
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.