NM_183235.3(RAB27A):c.244C>T (p.Arg82Cys) AND Griscelli syndrome type 2

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Nov 27, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000850516.9

Allele description [Variation Report for NM_183235.3(RAB27A):c.244C>T (p.Arg82Cys)]

NM_183235.3(RAB27A):c.244C>T (p.Arg82Cys)

Gene:

RAB27A:RAB27A, member RAS oncogene family [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

15q21.3

Genomic location:

Preferred name:

NM_183235.3(RAB27A):c.244C>T (p.Arg82Cys)

HGVS:

NC_000015.10:g.55228708G>A
NG_009103.1:g.66096C>T
NM_004580.5:c.244C>T
NM_183234.2:c.244C>T
NM_183235.3:c.244C>TMANE SELECT
NM_183236.3:c.244C>T
NP_004571.2:p.Arg82Cys
NP_899057.1:p.Arg82Cys
NP_899058.1:p.Arg82Cys
NP_899059.1:p.Arg82Cys
LRG_96:g.66096C>T
NC_000015.9:g.55520906G>A
NM_004580.4:c.244C>T

Protein change:

R82C

Links:

dbSNP: rs753966933

NCBI 1000 Genomes Browser:

rs753966933

Molecular consequence:

NM_004580.5:c.244C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_183234.2:c.244C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_183235.3:c.244C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_183236.3:c.244C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Griscelli syndrome type 2 (GS2)
Synonyms:: Griscelli syndrome with hemophagocytic syndrome; Partial albinism and immunodeficiency syndrome
Identifiers:: MONDO: MONDO:0011872; MedGen: C1868679; Orphanet: 381; Orphanet: 79477; OMIM: 607624

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000992720	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 12, 2018)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 27016801, 25741868
SCV001132924	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	no assertion criteria provided	Pathogenic (Aug 25, 2019)	germline	clinical testing
SCV001200879	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Nov 27, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 29357941, 32542393, 32856792, 32888943, 34329649, 27016801, 28492532
SCV002572134	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Aug 18, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 32542393, 29357941, 32375849, 27016801 Citation Link,
SCV003924277	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 8, 2023)	germline	research	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing, research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A founder RAB27A variant causes Griscelli syndrome type 2 with phenotypic heterogeneity in Qatari families.

Al-Sulaiman R, Othman A, El-Akouri K, Fareed S, AlMulla H, Sukik A, Al-Mureikhi M, Shahbeck N, Ali R, Al-Mesaifri F, Musa S, Al-Mulla M, Ibrahim K, Mohamed K, Al-Nesef MA, Ehlayel M, Ben-Omran T.

Am J Med Genet A. 2020 Nov;182(11):2570-2580. doi: 10.1002/ajmg.a.61829. Epub 2020 Aug 28.

PubMed [citation]

PMID:: 32856792

Efficacy and economics of targeted panel versus whole-exome sequencing in 878 patients with suspected primary immunodeficiency.

Platt CD, Zaman F, Bainter W, Stafstrom K, Almutairi A, Reigle M, Weeks S, Geha RS, Chou J; International Consortium for Immunodeficiencies..

J Allergy Clin Immunol. 2021 Feb;147(2):723-726. doi: 10.1016/j.jaci.2020.08.022. Epub 2020 Sep 2.

PubMed [citation]

PMID:: 32888943
PMCID:: PMC7870529

See all PubMed Citations (9)

Details of each submission

From Baylor Genetics, SCV000992720.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City, SCV001132924.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV001200879.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 82 of the RAB27A protein (p.Arg82Cys). This variant is present in population databases (rs753966933, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of Griscelli syndrome and/or hemophagocytic lymphohistiocytosis (PMID: 27016801, 29357941, 32542393, 32856792, 32888943, 34329649; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 419794). 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) performed at Invitae indicates that this missense variant is expected to disrupt RAB27A protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects RAB27A function (PMID: 27016801). 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002572134.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Variant summary: RAB27A c.244C>T (p.Arg82Cys) results in a non-conservative amino acid change located in the Small GTP-binding protein domain (IPR005225) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 250912 control chromosomes. c.244C>T has been reported in the literature as a homozygous or compound heterozygous genotype in multiple individuals reported with features of hemophagocytic lymphohistiocytosis (pHLH) or autosomal recessive Griscelli Syndrome type 2 (GS2) that can progress to HLH (example, Netter_2016, Jin_2018, Gadoury-Levesque_2020, Zhang_2020). At-least one of these publications reported two presumably unaffected homozygous siblings within a family with normal NK cell numbers but reduced CD107a mobilization, which could explain the severely decreased cytotoxic NK cell function (Netter_2016). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function demonstrating an inhibition in interaction of Rab27a with Munc13-4, but only partially effect on binding of Rab27a to melanophilin (Netter_2016). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely pathogenic, n=2; VUS, n=1; pathogenic, n=2). Some submitters cite overlapping evidence utilized in the context of this evalution. Based on the evidence outlined above, the variant was classified as likely pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, SCV003924277.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 19, 2024

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