VCV000504894.13 - ClinVar

NM_183235.3(RAB27A):c.149del (p.Arg50fs)

Germline

Classification

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.

(4)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_183235.3(RAB27A):c.149del (p.Arg50fs)

Variation ID: 504894 Accession: VCV000504894.13

Type and length

Deletion, 1 bp

Location

Cytogenetic: 15q21.3 15: 55234786 (GRCh38) [ NCBI UCSC ] 15: 55526984 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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 9, 2018	Oct 26, 2024	Oct 13, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_183235.3:c.149del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_899058.1:p.Arg50fs	frameshift
NM_004580.5:c.149del	NP_004571.2:p.Arg50fs	frameshift
NM_183234.2:c.149del	NP_899057.1:p.Arg50fs	frameshift
NM_183236.3:c.149del	NP_899059.1:p.Arg50fs	frameshift
NC_000015.10:g.55234786del
NC_000015.9:g.55526984del
NG_009103.1:g.60018del
LRG_96:g.60018del

... more HGVS ... less HGVS

Protein change

R50fs

Other names

Canonical SPDI

NC_000015.10:55234785:C:

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

The Genome Aggregation Database (gnomAD) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

Exome Aggregation Consortium (ExAC) 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00002

Links

ClinGen: CA7573699 dbSNP: rs770601673 VarSome

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
Gene	OMIM	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.
RAB27A		-	-	GRCh38 GRCh37	303	334

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.
Griscelli syndrome	Pathogenic (1)	criteria provided, single submitter	Feb 23, 2016	RCV000606194.4
Griscelli syndrome type 2	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Oct 13, 2024	RCV001860238.8

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.
Pathogenic (Feb 23, 2016)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	Griscelli syndrome (Autosomal recessive inheritance) Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000711776.2 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018	Publications: PubMed (5) PubMed: 10835631‚ 26684649‚ 19953648‚ 18350256‚ 16551969 Comment: The p.Arg50LysfsX35 variant in RAB27A has been reported in 4 individuals with Gr iscelli syndrome type 2 in the homozygous state (Menasche 2000). This variant … (more) The p.Arg50LysfsX35 variant in RAB27A has been reported in 4 individuals with Gr iscelli syndrome type 2 in the homozygous state (Menasche 2000). This variant ha s also been identified in 2/66,636 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). Although this variant has be en seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. The p.Arg50LysfsX35 variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 50 and leads to a premature termination codon 35 amino acids downstream . This alteration is then predicted to lead to a truncated or absent protein. In summary, this variant meets our criteria to be classified as pathogenic for Gri scelli syndrome type 2 in an autosomal recessive manner based upon case studies, low population frequency and functional prediction. (less) Number of individuals with the variant: 1
Pathogenic (May 25, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Griscelli syndrome type 2 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002808771.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Nov 17, 2020)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Griscelli syndrome type 2 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002196233.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 10835631‚ 12148598‚ 23160464 Comment: For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with Griscelli syndrome (PMID: 10835631, 12148598). ClinVar contains … (more) For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with Griscelli syndrome (PMID: 10835631, 12148598). ClinVar contains an entry for this variant (Variation ID: 504894). This variant is present in population databases (rs770601673, ExAC 0.003%). This sequence change creates a premature translational stop signal (p.Arg50Lysfs*35) in the RAB27A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RAB27A are known to be pathogenic (PMID: 10835631, 23160464). (less)
Pathogenic (Oct 13, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Griscelli syndrome type 2 Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV005375263.1 First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024	Comment: This sequence change creates a premature translational stop signal (GRCh38; NM_183236.3:c.149del:p.Arg50LysfsTer35) in the RAB27A protein. This alteration is expected to result in loss of function … (more) This sequence change creates a premature translational stop signal (GRCh38; NM_183236.3:c.149del:p.Arg50LysfsTer35) in the RAB27A protein. This alteration is expected to result in loss of function by premature termination codon resulting in protein truncation, or nonsense-mediated mRNA decay. This alteration is interpreted as disease-causing mutation, a commonly known mechanism for disease. Not observed at significant frequency in large population cohorts (gnomAD). This variant has a strong Conservation score. ClinVar contains an entry for this variant (Variation ID: 504894). This variant is associated with the following publications: PubMed: 12148598, 10835631, 23160464, 16551969, 18350256, 19953648, 26684649 In summary, this variant meets our criteria for classification as pathogenic based on the evidence outlined. (less)

Comment:

The p.Arg50LysfsX35 variant in RAB27A has been reported in 4 individuals with Gr iscelli syndrome type 2 in the homozygous state (Menasche 2000). This variant ha s also been identified in 2/66,636 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). Although this variant has be en seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. The p.Arg50LysfsX35 variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 50 and leads to a premature termination codon 35 amino acids downstream . This alteration is then predicted to lead to a truncated or absent protein. In summary, this variant meets our criteria to be classified as pathogenic for Gri scelli syndrome type 2 in an autosomal recessive manner based upon case studies, low population frequency and functional prediction.

Comment:

For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with Griscelli syndrome (PMID: 10835631, 12148598). ClinVar contains an entry for this variant (Variation ID: 504894). This variant is present in population databases (rs770601673, ExAC 0.003%). This sequence change creates a premature translational stop signal (p.Arg50Lysfs*35) in the RAB27A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RAB27A are known to be pathogenic (PMID: 10835631, 23160464).

Comment:

This sequence change creates a premature translational stop signal (GRCh38; NM_183236.3:c.149del:p.Arg50LysfsTer35) in the RAB27A protein. This alteration is expected to result in loss of function by premature termination codon resulting in protein truncation, or nonsense-mediated mRNA decay. This alteration is interpreted as disease-causing mutation, a commonly known mechanism for disease. Not observed at significant frequency in large population cohorts (gnomAD). This variant has a strong Conservation score. ClinVar contains an entry for this variant (Variation ID: 504894). This variant is associated with the following publications: PubMed: 12148598, 10835631, 23160464, 16551969, 18350256, 19953648, 26684649 In summary, this variant meets our criteria for classification as pathogenic based on the evidence outlined.

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Targeted high-throughput sequencing for genetic diagnostics of hemophagocytic lymphohistiocytosis.	Tesi B	Genome medicine	2015	PMID: 26684649
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
Clinical presentation of Griscelli syndrome type 2 and spectrum of RAB27A mutations.	Meeths M	Pediatric blood & cancer	2010	PMID: 19953648
Analysis of RAB27A gene in griscelli syndrome type 2: novel mutations including a deletion hotspot.	Mamishi S	Journal of clinical immunology	2008	PMID: 18350256
Lethal hemophagocytic lymphohistiocytosis in Hermansky-Pudlak syndrome type II.	Enders A	Blood	2006	PMID: 16551969
Griscelli disease: genotype-phenotype correlation in an array of clinical heterogeneity.	Sanal O	Journal of clinical immunology	2002	PMID: 12148598
Mutations in RAB27A cause Griscelli syndrome associated with haemophagocytic syndrome.	Ménasché G	Nature genetics	2000	PMID: 10835631

Text-mined citations for rs770601673 ...

These 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 Oct 27, 2024

ClinVar Genomic variation as it relates to human health

NM_183235.3(RAB27A):c.149del (p.Arg50fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs770601673 ...