ClinVar Genomic variation as it relates to human health
NM_032383.5(HPS3):c.1189C>T (p.Arg397Trp)
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_032383.5(HPS3):c.1189C>T (p.Arg397Trp)
Variation ID: 4613 Accession: VCV000004613.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3q24 3: 149150624 (GRCh38) [ NCBI UCSC ] 3: 148868411 (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 Feb 14, 2024 Sep 3, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_032383.5:c.1189C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_115759.2:p.Arg397Trp missense NM_001308258.2:c.694C>T NP_001295187.1:p.Arg232Trp missense NC_000003.12:g.149150624C>T NC_000003.11:g.148868411C>T NG_009847.1:g.26041C>T LRG_563:g.26041C>T LRG_563t1:c.1189C>T LRG_563p1:p.Arg397Trp Q969F9:p.Arg397Trp - Protein change
- R397W, R232W
- Other names
- R396W
- Canonical SPDI
- NC_000003.12:149150623:C:T
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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
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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 0.00004
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
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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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HPS3 | - | - |
GRCh38 GRCh37 |
897 | 1237 |
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
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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/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Sep 3, 2023 | RCV000004876.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 3, 2023 | RCV001070228.7 | |
Pathogenic (2) |
criteria provided, single submitter
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Jun 1, 2022 | RCV001272473.2 |
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
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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
(Jun 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hermansky-Pudlak syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002555926.1
First in ClinVar: Aug 08, 2022 Last updated: Aug 08, 2022 |
Comment:
Variant summary: HPS3 c.1189C>T (p.Arg397Trp) results in a non-conservative amino acid change located in the Hermansky-Pudlak syndrome 3, central region domain of the encoded protein … (more)
Variant summary: HPS3 c.1189C>T (p.Arg397Trp) results in a non-conservative amino acid change located in the Hermansky-Pudlak syndrome 3, central region domain 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 3.6e-05 in 251380 control chromosomes. c.1189C>T has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with Hermansky-Pudlak Syndrome (example Huizing_2001, Nazarian_2008, Wei_2016, Okamura_2019). These data indicate that the variant is very likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Two laboratories classified the variant as likely pathogenic and one as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(Mar 01, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hermansky-Pudlak syndrome 3
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002016628.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Sep 03, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hermansky-Pudlak syndrome 3
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004200003.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Sep 03, 2023)
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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: SCV001235446.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 397 of the HPS3 protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 397 of the HPS3 protein (p.Arg397Trp). This variant is present in population databases (rs121908316, gnomAD 0.006%). This missense change has been observed in individual(s) with Hermansky-Pudlak syndrome (PMID: 11590544, 27593200). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4613). 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 HPS3 protein function. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Nov 01, 2001)
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no assertion criteria provided
Method: literature only
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HERMANSKY-PUDLAK SYNDROME 3
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000025052.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 09, 2016 |
Comment on evidence:
Huizing et al. (2001) found a C-to-T transition at nucleotide 1329 of the HPS3 gene, which resulted in an arg396-to-trp (R396W) amino acid substitution, in … (more)
Huizing et al. (2001) found a C-to-T transition at nucleotide 1329 of the HPS3 gene, which resulted in an arg396-to-trp (R396W) amino acid substitution, in compound heterozygosity with 2729+1G-C (606118.0005) in a patient with Hermansky-Pudlak syndrome (HPS3; 614072). (less)
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Likely pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Hermansky-Pudlak syndrome
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001454535.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 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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NGS-based targeted resequencing identified rare subtypes of albinism: Providing accurate molecular diagnosis for Japanese patients with albinism. | Okamura K | Pigment cell & melanoma research | 2019 | PMID: 31141302 |
NGS-based 100-gene panel of hypopigmentation identifies mutations in Chinese Hermansky-Pudlak syndrome patients. | Wei A | Pigment cell & melanoma research | 2016 | PMID: 27593200 |
An immunoblotting assay to facilitate the molecular diagnosis of Hermansky-Pudlak syndrome. | Nazarian R | Molecular genetics and metabolism | 2008 | PMID: 17933573 |
Hermansky-Pudlak syndrome type 3 in Ashkenazi Jews and other non-Puerto Rican patients with hypopigmentation and platelet storage-pool deficiency. | Huizing M | American journal of human genetics | 2001 | PMID: 11590544 |
Text-mined citations for rs121908316 ...
HelpRecord last updated Mar 17, 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.