ClinVar Genomic variation as it relates to human health
NM_000195.5(HPS1):c.695C>T (p.Ala232Val)
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_000195.5(HPS1):c.695C>T (p.Ala232Val)
Variation ID: 298345 Accession: VCV000298345.10
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q24.2 10: 98430644 (GRCh38) [ NCBI UCSC ] 10: 100190401 (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 Dec 6, 2016 Nov 20, 2023 May 31, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000195.5:c.695C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000186.2:p.Ala232Val missense NM_001311345.2:c.-179C>T 5 prime UTR NM_001322476.2:c.695C>T NP_001309405.1:p.Ala232Val missense NM_001322477.2:c.695C>T NP_001309406.1:p.Ala232Val missense NM_001322478.2:c.695C>T NP_001309407.1:p.Ala232Val missense NM_001322479.2:c.695C>T NP_001309408.1:p.Ala232Val missense NM_001322480.2:c.434C>T NP_001309409.1:p.Ala145Val missense NM_001322481.2:c.434C>T NP_001309410.1:p.Ala145Val missense NM_001322482.2:c.434C>T NP_001309411.1:p.Ala145Val missense NM_001322483.2:c.326C>T NP_001309412.1:p.Ala109Val missense NM_001322484.2:c.326C>T NP_001309413.1:p.Ala109Val missense NM_001322485.2:c.326C>T NP_001309414.1:p.Ala109Val missense NM_001322487.2:c.-278C>T 5 prime UTR NM_001322489.2:c.-179C>T 5 prime UTR NM_001322490.2:c.577C>T NP_001309419.1:p.Pro193Ser missense NM_001322491.2:c.695C>T NP_001309420.1:p.Ala232Val missense NM_001322492.2:c.577C>T NP_001309421.1:p.Pro193Ser missense NM_182639.4:c.695C>T NP_872577.1:p.Ala232Val missense NC_000010.11:g.98430644G>A NC_000010.10:g.100190401G>A NG_009646.1:g.21304C>T LRG_562:g.21304C>T LRG_562t1:c.695C>T LRG_562p1:p.Ala232Val - Protein change
- A232V, P193S, A145V, A109V
- Other names
- NM_000195.5(HPS1):c.695C>T
- p.Ala232Val
- Canonical SPDI
- NC_000010.11:98430643:G:A
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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.
The Genome Aggregation Database (gnomAD) 0.00006
Trans-Omics for Precision Medicine (TOPMed) 0.00006
The Genome Aggregation Database (gnomAD), exomes 0.00008
Exome Aggregation Consortium (ExAC) 0.00009
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 | ||
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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
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. |
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HPS1 | - | - |
GRCh38 GRCh37 |
1085 | 1117 |
Conditions - Germline
Condition
Help
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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Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Apr 25, 2022 | RCV000309402.6 | |
Uncertain significance (1) |
criteria provided, single submitter
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May 31, 2023 | RCV003401283.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Nov 29, 2021 | RCV001828293.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 23, 2022 | RCV001844115.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 18, 2022 | RCV002520518.1 |
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. |
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Uncertain significance
(Jan 12, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hermansky-Pudlak syndrome 1
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000359665.3
First in ClinVar: Dec 06, 2016 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
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Uncertain significance
(Nov 29, 2021)
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criteria provided, single submitter
Method: curation
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Hermansky-Pudlak syndrome
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV002097062.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022 |
Comment:
The p.Ala232Val variant in HPS1 has been reported in 1 individual, in the homozygous state, with Hermansky-Pudlak syndrome (PMID: 26785811) and has been identified in … (more)
The p.Ala232Val variant in HPS1 has been reported in 1 individual, in the homozygous state, with Hermansky-Pudlak syndrome (PMID: 26785811) and has been identified in 0.03% (4/8856) of Ashkenazi Jewish chromosomes (including one homozygous occurrence) by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs764420988). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID#: 298345) and has been interpreted as VUS by Illumina Clinical Services Laboratory (Illumina). Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Ala232Val variant is uncertain. ACMG/AMP Criteria applied: BP4, PM3_supporting (Richards 2015). (less)
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Uncertain significance
(Feb 23, 2022)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002103400.1
First in ClinVar: Mar 12, 2022 Last updated: Mar 12, 2022 |
Comment:
Variant summary: HPS1 c.695C>T (p.Ala232Val) results in a non-conservative amino acid change located in the FUZ/MON1/HPS1, second Longin domain (IPR043971) of the encoded protein sequence. … (more)
Variant summary: HPS1 c.695C>T (p.Ala232Val) results in a non-conservative amino acid change located in the FUZ/MON1/HPS1, second Longin domain (IPR043971) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-05 in 160342 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than expected for a pathogenic variant in HPS1 causing Hermansky-Pudlak Syndrome (8.1e-05 vs 0.00096), allowing no conclusion about variant significance. c.695C>T has been reported in the literature in a homozygous individual affected with oculocutaneous albinism (Khan_2016). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. (less)
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Uncertain significance
(Apr 25, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hermansky-Pudlak syndrome 1
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002782567.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(Oct 18, 2022)
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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: SCV003522602.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 232 of the HPS1 protein (p.Ala232Val). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 232 of the HPS1 protein (p.Ala232Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with oculocutaneous albinism (PMID: 26785811). ClinVar contains an entry for this variant (Variation ID: 298345). 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 not expected to disrupt HPS1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(May 31, 2023)
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criteria provided, single submitter
Method: clinical testing
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HPS1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004104062.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The HPS1 c.695C>T variant is predicted to result in the amino acid substitution p.Ala232Val. This variant was reported in homozygous state in an individual with … (more)
The HPS1 c.695C>T variant is predicted to result in the amino acid substitution p.Ala232Val. This variant was reported in homozygous state in an individual with albinism (Khan et al 2016. PubMed ID: 26785811). This variant is reported in 0.034% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-100190401-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (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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Hermansky-Pudlak syndrome genes are frequently mutated in patients with albinism from the Arabian Peninsula. | Khan AO | Clinical genetics | 2016 | PMID: 26785811 |
Text-mined citations for rs764420988 ...
HelpRecord last updated Mar 30, 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.