ClinVar Genomic variation as it relates to human health
NM_000066.4(C8B):c.1282C>T (p.Arg428Ter)
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_000066.4(C8B):c.1282C>T (p.Arg428Ter)
Variation ID: 17038 Accession: VCV000017038.40
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p32.2 1: 56940965 (GRCh38) [ NCBI UCSC ] 1: 57406638 (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 4, 2013 May 12, 2024 Jan 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000066.4:c.1282C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000057.3:p.Arg428Ter nonsense NM_001278543.2:c.1126C>T NP_001265472.2:p.Arg376Ter nonsense NM_001278544.2:c.1096C>T NP_001265473.2:p.Arg366Ter nonsense NC_000001.11:g.56940965G>A NC_000001.10:g.57406638G>A NG_007285.1:g.30051C>T LRG_31:g.30051C>T LRG_31t1:c.1282C>T - Protein change
- R428*, R376*, R366*
- Other names
- C8B, ARG428TER
- Canonical SPDI
- NC_000001.11:56940964: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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0.00120 (A)
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Allele frequency
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The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00109
The Genome Aggregation Database (gnomAD) 0.00118
1000 Genomes Project 0.00120
1000 Genomes Project 30x 0.00125
Trans-Omics for Precision Medicine (TOPMed) 0.00127
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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C8B | - | - |
GRCh38 GRCh37 |
351 | 364 |
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
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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. |
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Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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May 8, 2023 | RCV000018566.38 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 24, 2014 | RCV000844619.5 | |
Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
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Jan 31, 2024 | RCV000578926.27 | |
C8B-related condition
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Pathogenic (1) |
criteria provided, single submitter
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Jun 13, 2023 | RCV003398541.4 |
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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Pathogenic
(Aug 08, 2018)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000862850.1
First in ClinVar: Feb 13, 2018 Last updated: Feb 13, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(Apr 24, 2014)
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criteria provided, single submitter
Method: clinical testing
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Complement component 6 deficiency
(Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000245585.2
First in ClinVar: Sep 14, 2015 Last updated: Aug 31, 2019 |
Comment:
The p.Arg428X variant in C8B has been reported in multiple individuals with clin ical features of C8B deficiency, including in >20 individuals who were homozygou … (more)
The p.Arg428X variant in C8B has been reported in multiple individuals with clin ical features of C8B deficiency, including in >20 individuals who were homozygou s for this variant (Kaufmann, 1993; Saucedo, 1995). Homozygous and compound hete rozygous individuals were shown to have absent C8? activity. This variant has be en identified in 0.17% (112/66,626) of European chromosomes by the Exome Aggrega tion Consortium (ExAC, http://exac.broadinstitute.org; dbSNP: rs41286844). This nonsense variant leads to a premature termination codon at position 428 which is predicted to lead to a truncated or absent protein. In summary, this variant me ets criteria to be classified as pathogenic based on case observations, function al evidence and predicted protein impact. (less)
Number of individuals with the variant: 2
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Pathogenic
(Nov 27, 2019)
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criteria provided, single submitter
Method: clinical testing
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Type II complement component 8 deficiency
Affected status: yes
Allele origin:
unknown
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Baylor Genetics
Accession: SCV001522817.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
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Pathogenic
(Jun 13, 2023)
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criteria provided, single submitter
Method: clinical testing
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C8B-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004104123.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The C8B c.1282C>T variant is predicted to result in premature protein termination (p.Arg428*). This variant has been reported in the homozygous and compound heterozygous state … (more)
The C8B c.1282C>T variant is predicted to result in premature protein termination (p.Arg428*). This variant has been reported in the homozygous and compound heterozygous state as causative for C8 deficiency (Kaufmann et al. 1993. PubMed ID: 8098723; Dellepiane et al. 2016. PubMed ID: 27183977). This variant is reported in 0.19% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-57406638-G-A). Nonsense variants in C8B are expected to be pathogenic, and this variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/17038). This variant is interpreted as pathogenic. (less)
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Pathogenic
(Sep 01, 2021)
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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: SCV001961115.15
First in ClinVar: Oct 08, 2021 Last updated: May 12, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Jul 29, 2021)
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criteria provided, single submitter
Method: clinical testing
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Type II complement component 8 deficiency
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002809682.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Jul 15, 2022)
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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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GeneDx
Accession: SCV000680777.5
First in ClinVar: Feb 13, 2018 Last updated: Mar 04, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 29431110, 30609409, 31028847, 9476133, 14767900, 28192236, 8098723, 27183977, 25525159, 7594510, 19434484, 8020197, 9165271, 34426522, 31589614, 28368462, 33726816) (less)
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Pathogenic
(May 08, 2023)
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criteria provided, single submitter
Method: research
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Type II complement component 8 deficiency
Affected status: yes
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV003924312.1
First in ClinVar: May 20, 2023 Last updated: May 20, 2023 |
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Pathogenic
(Mar 28, 2023)
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criteria provided, single submitter
Method: clinical testing
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Type II complement component 8 deficiency
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002018020.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 31, 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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Invitae
Accession: SCV002240755.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg428*) in the C8B gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg428*) in the C8B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in C8B are known to be pathogenic (PMID: 7594510). This variant is present in population databases (rs41286844, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with C8B deficiency (PMID: 8098723, 27183977). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17038). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Sep 01, 2009)
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no assertion criteria provided
Method: literature only
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COMPLEMENT C8 DEFICIENCY, TYPE II
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000038848.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 16, 2021 |
Comment on evidence:
In all 7 affected members of 5 Caucasian families segregating C8 deficiency (C8D2; 613789), Kaufmann et al. (1993) identified a C-to-T transition in exon 9 … (more)
In all 7 affected members of 5 Caucasian families segregating C8 deficiency (C8D2; 613789), Kaufmann et al. (1993) identified a C-to-T transition in exon 9 of the C8B gene, leading to the creation of a stop codon; CGA (arg) was changed to TGA (stop) at nucleotide position 1309. The codon involved was 374, according to Kaufmann (1993), resulting in an ARG374TER substitution. The authors noted that the mutation occurred at a CpG dinucleotide. Five patients were homozygous for the mutation; in 2 the mutation was found on only 1 chromosome and the other mutation was not identified. In 2 patients with C8B deficiency from Switzerland and Poland, Rao et al. (2004) identified compound heterozygosity for the exon 9 C-T transition and another missense mutation in the C8B gene. The Swiss patient also had a 298C-T transition in exon 3 (Q91X; 120960.0004), and the Polish patient also had a 388C-T transition in exon 3 (R121X; 120960.0003). In their Table 2, Arnold et al. (2009) reported that this mutation should be designated 1282C-T rather than 1309C-T. The correct amino acid substitution is arg428 to ter (R428X). (less)
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Pathogenic
(Aug 13, 2019)
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no assertion criteria provided
Method: clinical testing
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Type II complement component 8 deficiency
Affected status: yes
Allele origin:
germline
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Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare
Accession: SCV001192615.1
First in ClinVar: Mar 29, 2020 Last updated: Mar 29, 2020 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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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: SCV001952338.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001963103.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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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: SCV001965677.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
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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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Invasive meningococcal disease in three siblings with hereditary deficiency of the 8(th) component of complement: evidence for the importance of an early diagnosis. | Dellepiane RM | Orphanet journal of rare diseases | 2016 | PMID: 27183977 |
A novel mutation in a patient with a deficiency of the eighth component of complement associated with recurrent meningococcal meningitis. | Arnold DF | Journal of clinical immunology | 2009 | PMID: 19434484 |
[Further study on heterogeneic basis of complement C8 beta deficiency]. | Rao L | Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics | 2004 | PMID: 14767900 |
Delineation of additional genetic bases for C8 beta deficiency. Prevalence of null alleles and predominance of C-->T transition in their genesis. | Saucedo L | Journal of immunology (Baltimore, Md. : 1950) | 1995 | PMID: 7594510 |
The human complement component C8B gene: structure and phylogenetic relationship. | Kaufmann T | Human genetics | 1993 | PMID: 8365729 |
Genetic basis of human complement C8 beta deficiency. | Kaufmann T | Journal of immunology (Baltimore, Md. : 1950) | 1993 | PMID: 8098723 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=C8B | - | - | - | - |
Text-mined citations for rs41286844 ...
HelpRecord last updated May 12, 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.