ClinVar Genomic variation as it relates to human health
NM_001355436.2(SPTB):c.5266C>T (p.Arg1756Ter)
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_001355436.2(SPTB):c.5266C>T (p.Arg1756Ter)
Variation ID: 12843 Accession: VCV000012843.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q23.3 14: 64772867 (GRCh38) [ NCBI UCSC ] 14: 65239585 (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 Apr 28, 2018 Jun 2, 2024 Nov 16, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001355436.2:c.5266C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001342365.1:p.Arg1756Ter nonsense NM_001024858.4:c.5266C>T NP_001020029.1:p.Arg1756Ter nonsense NM_001355437.2:c.5266C>T NP_001342366.1:p.Arg1756Ter nonsense NC_000014.9:g.64772867G>A NC_000014.8:g.65239585G>A NG_016202.2:g.112026C>T LRG_1130:g.112026C>T LRG_1130t1:c.5266C>T LRG_1130p1:p.Arg1756Ter LRG_1130t2:c.5266C>T LRG_1130p2:p.Arg1756Ter - Protein change
- R1756*
- Other names
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- Canonical SPDI
- NC_000014.9:64772866: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.
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- 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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| SPTB | - | - |
GRCh38 GRCh37 |
1023 | 1055 | |
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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Jul 28, 2022 | RCV000013696.23 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Nov 16, 2023 | RCV001508363.13 |
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
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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
(Apr 07, 2022)
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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: SCV003800565.2
First in ClinVar: Feb 13, 2023 Last updated: Mar 04, 2023 |
Comment:
The SPTB c.5266C>T; p.Arg1756 variant (rs267607086) is reported in the literature in at least 12 individuals affected with hereditary spherocytosis (Aggarwal 2020, Maciag 2009, Park … (more)
The SPTB c.5266C>T; p.Arg1756 variant (rs267607086) is reported in the literature in at least 12 individuals affected with hereditary spherocytosis (Aggarwal 2020, Maciag 2009, Park 2016, Tole 2020). This variant is also reported in ClinVar (Variation ID: 12843). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. (less)
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Pathogenic
(Apr 18, 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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Revvity Omics, Revvity
Accession: SCV003819675.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Nov 16, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003442309.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg1756*) in the SPTB gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg1756*) in the SPTB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SPTB are known to be pathogenic (PMID: 1391962, 1498324, 8844207, 26830532, 27292444). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with hereditary spherocytosis (PMID: 19538529, 26830532, 31602632, 32436265). ClinVar contains an entry for this variant (Variation ID: 12843). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Feb 22, 2019)
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criteria provided, single submitter
Method: clinical testing
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SPHEROCYTOSIS, TYPE 2
Affected status: yes
Allele origin:
germline
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Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV000996251.1
First in ClinVar: Oct 19, 2019 Last updated: Oct 19, 2019 |
Comment:
This nonsense variant found in exon 25 of 35 is predicted to result in loss of normal protein function. This variant has been previously reported … (more)
This nonsense variant found in exon 25 of 35 is predicted to result in loss of normal protein function. This variant has been previously reported as heterozygous change in patients with hereditary spherocytosis (PMID 19538529, 26830532). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.5266C>T, p.Arg1756Ter variant is classified as Pathogenic. (less)
Number of individuals with the variant: 1
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Pathogenic
(Jul 28, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary spherocytosis type 2
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002581079.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PVS1, PS3_MOD, PS4_MOD, PM6, PM2_SUP, PP1, PP4
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Number of individuals with the variant: 1
Sex: female
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Pathogenic
(Apr 18, 2022)
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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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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001714475.2
First in ClinVar: Jun 15, 2021 Last updated: Jun 02, 2024 |
Comment:
PVS1_strong, PS4, PM2, PS3
Number of individuals with the variant: 3
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Pathogenic
(Aug 01, 2009)
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no assertion criteria provided
Method: literature only
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SPHEROCYTOSIS, TYPE 2, AUTOSOMAL DOMINANT
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000033943.4
First in ClinVar: Apr 04, 2013 Last updated: Apr 23, 2022 |
Comment on evidence:
In sibs with hereditary spherocytosis (SPH2; 616649), Maciag et al. (2009) found an approximately 25% decrease in SPTB mRNA compared to controls. Direct sequencing of … (more)
In sibs with hereditary spherocytosis (SPH2; 616649), Maciag et al. (2009) found an approximately 25% decrease in SPTB mRNA compared to controls. Direct sequencing of the SPTB gene identified a heterozygous 5268C-T transition in exon 26, resulting in an arg1756-to-ter (R1756X) substitution. The findings suggested that the mutation did not lead to complete nonsense-mediated mRNA decay, perhaps because of its location. Maciag et al. (2009) postulated that the shortened protein was incorporated into the erythrocyte membrane, leading to mechanical instability. (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
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Genotype-phenotype correlation in children with hereditary spherocytosis. | Tole S | British journal of haematology | 2020 | PMID: 32436265 |
| Deciphering molecular heterogeneity of Indian families with hereditary spherocytosis using targeted next-generation sequencing: First South Asian study. | Aggarwal A | British journal of haematology | 2020 | PMID: 31602632 |
| Clinical utility of next-generation sequencing in the diagnosis of hereditary haemolytic anaemias. | Agarwal AM | British journal of haematology | 2016 | PMID: 27292444 |
| Mutational characteristics of ANK1 and SPTB genes in hereditary spherocytosis. | Park J | Clinical genetics | 2016 | PMID: 26830532 |
| Novel beta-spectrin mutations in hereditary spherocytosis associated with decreased levels of mRNA. | Maciag M | British journal of haematology | 2009 | PMID: 19538529 |
| Spectrin mutations in hereditary elliptocytosis and hereditary spherocytosis. | Maillet P | Human mutation | 1996 | PMID: 8844207 |
| Spectrin beta Tandil, a novel shortened beta-chain variant associated with hereditary elliptocytosis is due to a deletional frameshift mutation in the beta-spectrin gene. | Garbarz M | Blood | 1992 | PMID: 1498324 |
| A deletional frameshift mutation of the beta-spectrin gene associated with elliptocytosis in spectrin Tokyo (beta 220/216). | Kanzaki A | Blood | 1992 | PMID: 1391962 |
Text-mined citations for rs267607086 ...
HelpRecord 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.