VCV000235346.23 - ClinVar

NM_183235.3(RAB27A):c.560G>A (p.Arg187Gln)

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.

(8)

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.

Conflicting classifications of pathogenicity
Uncertain significance(6); Likely benign(2)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_183235.3(RAB27A):c.560G>A (p.Arg187Gln)

Variation ID: 235346 Accession: VCV000235346.23

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 15q21.3 15: 55205613 (GRCh38) [ NCBI UCSC ] 15: 55497811 (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	Jun 9, 2016	Jul 15, 2024	Apr 26, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_183235.3:c.560G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_899058.1:p.Arg187Gln	missense
NM_004580.5:c.560G>A	NP_004571.2:p.Arg187Gln	missense
NM_183234.2:c.560G>A	NP_899057.1:p.Arg187Gln	missense
NM_183236.3:c.560G>A	NP_899059.1:p.Arg187Gln	missense
NC_000015.10:g.55205613C>T
NC_000015.9:g.55497811C>T
NG_009103.1:g.89191G>A
LRG_96:g.89191G>A

... more HGVS ... less HGVS

Protein change

R187Q

Other names

Canonical SPDI

NC_000015.10:55205612:C:T

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.

0.00180 (T)

Allele frequency Help The frequency of the allele represented by this VCV record.

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

The Genome Aggregation Database (gnomAD) 0.00022

Trans-Omics for Precision Medicine (TOPMed) 0.00036

Exome Aggregation Consortium (ExAC) 0.00044

The Genome Aggregation Database (gnomAD), exomes 0.00052

1000 Genomes Project 0.00180

1000 Genomes Project 30x 0.00187

Links

ClinGen: CA7573530 dbSNP: rs182849552 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.
not provided	Uncertain significance (1)	criteria provided, single submitter	Jun 2, 2015	RCV000224304.4
Griscelli syndrome type 2	Conflicting interpretations of pathogenicity (4)	criteria provided, conflicting classifications	Jan 26, 2024	RCV001027844.18
Autoinflammatory syndrome	Uncertain significance (1)	criteria provided, single submitter	Apr 1, 2020	RCV002262831.3
RAB27A-related disorder	Uncertain significance (1)	criteria provided, single submitter	Dec 21, 2022	RCV003401158.4
not specified	Uncertain significance (1)	criteria provided, single submitter	Apr 26, 2024	RCV004586640.1

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.
Uncertain Significance (Jun 02, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics Accession: SCV000280851.1 First in ClinVar: Jun 09, 2016 Last updated: Jun 09, 2016	Comment: Converted during submission to Uncertain significance.
Likely benign (Jan 12, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Griscelli syndrome type 2 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001279918.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. (less)
Uncertain significance (Apr 01, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autoinflammatory syndrome Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, The Hospital for Sick Children Accession: SCV002542935.1 First in ClinVar: Jul 09, 2022 Last updated: Jul 09, 2022
Uncertain significance (Dec 22, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Griscelli syndrome type 2 Affected status: unknown Allele origin: germline	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago Accession: SCV001190464.2 First in ClinVar: Mar 26, 2020 Last updated: May 06, 2023	Comment: RAB27A NM_004580.4 exon6 p.Arg187Gln (c.560G>A): This variant has been reported in the literature in the heterozygous state in at least two individuals affected by refractory … (more) RAB27A NM_004580.4 exon6 p.Arg187Gln (c.560G>A): This variant has been reported in the literature in the heterozygous state in at least two individuals affected by refractory hemophagocytic lymphohistiocytosis, with no second variant in RAB27A identified (Zhao 2019 PMID:31164711). This variant is also present in 0.6% (137/19954) of East Asian alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/15-55497811-C-T) and is present in ClinVar (Variation ID:235346). Computational predictive tools for this variant are unclear. Splice prediction tools suggest that this variant may affect splicing. However, further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. (less)
Uncertain significance (Dec 21, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	RAB27A-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004104550.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The RAB27A c.560G>A variant is predicted to result in the amino acid substitution p.Arg187Gln. This variant has been reported in the heterozygous state in two … (more) The RAB27A c.560G>A variant is predicted to result in the amino acid substitution p.Arg187Gln. This variant has been reported in the heterozygous state in two individuals with hemophagocytic lymphohistiocytosis and one individual with a chronic active EBV infection of T/NK-cell type (Zhao Y et al. 2019. PubMed ID: 31164711; Table 2, Gao L et al. 2021. PubMed ID: 34185399; Table S1, Guan YQ et al. 2021. PubMed ID: 34170459). In both individuals with hemophagocytic lymphohistiocytosis, this variant was reported to be inherited, in one case from a parent who was noted to have impaired NK cytotoxicity function (Figure 2, Zhao Y et al. 2019. PubMed ID: 31164711; Table 2, Gao L et al. 2021. PubMed ID: 34185399). This variant is reported in 0.69% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-55497811-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
Uncertain significance (Nov 10, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Griscelli syndrome type 2 Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003810449.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Likely benign (Jan 26, 2024)	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: SCV001038438.6 First in ClinVar: Dec 17, 2019 Last updated: Feb 20, 2024
Uncertain significance (Apr 26, 2024)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV005076387.1 First in ClinVar: Jul 15, 2024 Last updated: Jul 15, 2024	Publications: PubMed (3) PubMed: 34170459‚ 31164711‚ 37273692 Comment: Variant summary: RAB27A c.560G>A (p.Arg187Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign … (more) Variant summary: RAB27A c.560G>A (p.Arg187Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00052 in 251456 control chromosomes (gnomAD). c.560G>A has been reported in the literature in individuals affected with Haemophagocytic lymphohistiocytosis or Menieres disease without strong evidence of causality (Zhao_2020, Guan_2021, Zou_2023). These reports do not provide unequivocal conclusions about association of the variant with Griscelli Syndrome Type 2. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31164711, 34170459, 37273692). ClinVar contains an entry for this variant (Variation ID: 235346). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

Comment:

RAB27A NM_004580.4 exon6 p.Arg187Gln (c.560G>A): This variant has been reported in the literature in the heterozygous state in at least two individuals affected by refractory hemophagocytic lymphohistiocytosis, with no second variant in RAB27A identified (Zhao 2019 PMID:31164711). This variant is also present in 0.6% (137/19954) of East Asian alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/15-55497811-C-T) and is present in ClinVar (Variation ID:235346). Computational predictive tools for this variant are unclear. Splice prediction tools suggest that this variant may affect splicing. However, further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.

Comment:

The RAB27A c.560G>A variant is predicted to result in the amino acid substitution p.Arg187Gln. This variant has been reported in the heterozygous state in two individuals with hemophagocytic lymphohistiocytosis and one individual with a chronic active EBV infection of T/NK-cell type (Zhao Y et al. 2019. PubMed ID: 31164711; Table 2, Gao L et al. 2021. PubMed ID: 34185399; Table S1, Guan YQ et al. 2021. PubMed ID: 34170459). In both individuals with hemophagocytic lymphohistiocytosis, this variant was reported to be inherited, in one case from a parent who was noted to have impaired NK cytotoxicity function (Figure 2, Zhao Y et al. 2019. PubMed ID: 31164711; Table 2, Gao L et al. 2021. PubMed ID: 34185399). This variant is reported in 0.69% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-55497811-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Comment:

Variant summary: RAB27A c.560G>A (p.Arg187Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00052 in 251456 control chromosomes (gnomAD). c.560G>A has been reported in the literature in individuals affected with Haemophagocytic lymphohistiocytosis or Menieres disease without strong evidence of causality (Zhao_2020, Guan_2021, Zou_2023). These reports do not provide unequivocal conclusions about association of the variant with Griscelli Syndrome Type 2. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31164711, 34170459, 37273692). ClinVar contains an entry for this variant (Variation ID: 235346). Based on the evidence outlined above, the variant was classified as uncertain significance.

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
Multiple genetic variants involved in both autoimmunity and autoinflammation detected in Chinese patients with sporadic Meniere's disease: a preliminary study.	Zou J	Frontiers in neurology	2023	PMID: 37273692
Inherited Genetic Susceptibility to Nonimmunosuppressed Epstein-Barr Virus-associated T/NK-cell Lymphoproliferative Diseases in Chinese Patients.	Guan YQ	Current medical science	2021	PMID: 34170459
Salvage therapy with dose-escalating ruxolitinib as a bridge to allogeneic stem cell transplantation for refractory hemophagocytic lymphohistiocytosis.	Zhao Y	Bone marrow transplantation	2020	PMID: 31164711

Text-mined citations for rs182849552 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_183235.3(RAB27A):c.560G>A (p.Arg187Gln)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs182849552 ...