ClinVar Genomic variation as it relates to human health
NM_183235.3(RAB27A):c.467+1G>C
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_183235.3(RAB27A):c.467+1G>C
Variation ID: 582014 Accession: VCV000582014.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q21.3 15: 55223888 (GRCh38) [ NCBI UCSC ] 15: 55516086 (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 Jul 8, 2017 Feb 7, 2023 Oct 13, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_183235.3:c.467+1G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NM_004580.5:c.467+1G>C splice donor NM_183234.2:c.467+1G>C splice donor NM_183236.3:c.467+1G>C splice donor NC_000015.10:g.55223888C>G NC_000015.9:g.55516086C>G NG_009103.1:g.70916G>C LRG_96:g.70916G>C - Protein change
- Other names
- IVS5, G-C, +1
- Canonical SPDI
- NC_000015.10:55223887:C: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
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
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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RAB27A | - | - |
GRCh38 GRCh37 |
296 | 327 |
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
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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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Oct 13, 2022 | RCV000705980.9 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 5, 2020 | RCV002252221.2 |
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
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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
(Feb 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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Griscelli syndrome type 2
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002103760.1
First in ClinVar: Mar 12, 2022 Last updated: Mar 12, 2022 |
Comment:
Variant summary: RAB27A c.467+1G>C is located in a canonical splice-site at the junction of the penultimate exon and the last intron, and is predicted to … (more)
Variant summary: RAB27A c.467+1G>C is located in a canonical splice-site at the junction of the penultimate exon and the last intron, and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251162 control chromosomes (gnomAD). c.467+1G>C has been reported in the literature in multiple homozygous- and a compound heterozygous individuals affected with Griscelli Syndrome Type 2 (e.g. Menasche_2000, Sepulveda_2012, Bizario_2004, Gironi_2019, Blincoe_2020). In one of the compound heterozygous patients, who carried a nonsense variant in trans, a strong deficiency in CD8+ T cell cytotoxicity was demonstrated, which could be rescued by RAB27A gene transfer (Bizario_2004). These data indicate that the variant is very likely to be associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(Jan 05, 2020)
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criteria provided, single submitter
Method: clinical testing
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See cases
Affected status: yes
Allele origin:
germline
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Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002523448.1
First in ClinVar: Jun 09, 2022 Last updated: Jun 09, 2022 |
Comment:
ACMG classification criteria: PVS1, PS4, PM2, PM3
Clinical Features:
Recurrent respiratory infections (present) , Hypopigmentation of hair (present) , Generalized hypopigmentation (present) , Bronchiectasis (present)
Geographic origin: Brazil
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Pathogenic
(Oct 13, 2022)
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criteria provided, single submitter
Method: clinical testing
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Griscelli syndrome type 2
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000835006.3
First in ClinVar: Oct 10, 2018 Last updated: Feb 07, 2023 |
Comment:
This sequence change affects a donor splice site in intron 5 of the RAB27A gene. While this variant is not anticipated to result in nonsense … (more)
This sequence change affects a donor splice site in intron 5 of the RAB27A gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of Griscelli syndrome type 2 (PMID: 10835631, 15163896, 30104219, 30934652). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 582014). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jul 01, 2004)
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no assertion criteria provided
Method: literature only
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GRISCELLI SYNDROME, TYPE 2
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000026537.4
First in ClinVar: Apr 04, 2013 Last updated: Jun 05, 2022 |
Comment on evidence:
In a patient with Griscelli syndrome type 2 (GS2; 607624), Menasche et al. (2000) identified a homozygous G-to-C transversion at the +1 position of the … (more)
In a patient with Griscelli syndrome type 2 (GS2; 607624), Menasche et al. (2000) identified a homozygous G-to-C transversion at the +1 position of the splice donor site of exon 5 of the RAB27A gene, predicted to result in exon skipping or the use of an alternative splice site. In a 4-year-old Brazilian boy with Griscelli syndrome type 2, Bizario et al. (2004) identified compound heterozygosity for the G-to-C transversion in intron 5 (467+1G-C) and a nonsense mutation inherited from the father (603868.0009). Bizario et al. (2004) found that both the mother of their patient and the mother of the patient of Menasche et al. (2000) were heterozygous for the G467+1C mutation and shared the same marker haplotypes, findings compatible with the mutation being inherited from a common ancestor. (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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Neuroinflammatory Disease as an Isolated Manifestation of Hemophagocytic Lymphohistiocytosis. | Blincoe A | Journal of clinical immunology | 2020 | PMID: 32638196 |
Congenital Hypopigmentary Disorders with Multiorgan Impairment: A Case Report and an Overview on Gray Hair Syndromes. | Gironi LC | Medicina (Kaunas, Lithuania) | 2019 | PMID: 30934652 |
Treatment dilemmas in asymptomatic children with primary hemophagocytic lymphohistiocytosis. | Lucchini G | Blood | 2018 | PMID: 30104219 |
Distinct severity of HLH in both human and murine mutants with complete loss of cytotoxic effector PRF1, RAB27A, and STX11. | Sepulveda FE | Blood | 2013 | PMID: 23160464 |
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
Griscelli syndrome: characterization of a new mutation and rescue of T-cytotoxic activity by retroviral transfer of RAB27A gene. | Bizario JC | Journal of clinical immunology | 2004 | PMID: 15163896 |
Mutations in RAB27A cause Griscelli syndrome associated with haemophagocytic syndrome. | Ménasché G | Nature genetics | 2000 | PMID: 10835631 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
Text-mined citations for rs756071120 ...
HelpRecord last updated Jun 10, 2023
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.