ClinVar Genomic variation as it relates to human health
NM_173477.5(USH1G):c.83C>T (p.Pro28Leu)
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.
Uncertain significance(5); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_173477.5(USH1G):c.83C>T (p.Pro28Leu)
Variation ID: 48139 Accession: VCV000048139.25
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q25.1 17: 74922991 (GRCh38) [ NCBI UCSC ] 17: 72919086 (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 Jan 31, 2015 Feb 7, 2023 Oct 17, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_173477.5:c.83C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_775748.2:p.Pro28Leu missense NM_001282489.3:c.-174C>T 5 prime UTR NC_000017.11:g.74922991G>A NC_000017.10:g.72919086G>A NG_007882.2:g.5273C>T NG_033062.2:g.3717G>A LRG_1416:g.5273C>T LRG_1416t1:c.83C>T LRG_1416p1:p.Pro28Leu - Protein change
- P28L
- Other names
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- Canonical SPDI
- NC_000017.11:74922990: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
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00065
Trans-Omics for Precision Medicine (TOPMed) 0.00070
The Genome Aggregation Database (gnomAD), exomes 0.00076
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00108
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
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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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USH1G | - | - |
GRCh38 GRCh37 |
414 | 442 |
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 (1) |
criteria provided, single submitter
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Apr 7, 2020 | RCV000041427.7 | |
Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
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Oct 17, 2022 | RCV000432648.13 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jul 30, 2021 | RCV001127509.9 |
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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Uncertain significance
(Oct 17, 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: SCV001234492.3
First in ClinVar: Apr 15, 2020 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 28 of the USH1G protein (p.Pro28Leu). … (more)
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 28 of the USH1G protein (p.Pro28Leu). This variant is present in population databases (rs145448362, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Usher syndrome or retinitis pigmentosa (PMID: 17896313, 22135276, 28224992). ClinVar contains an entry for this variant (Variation ID: 48139). 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 USH1G 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
(Jan 25, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000510711.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
Comment:
Converted during submission to Uncertain significance.
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Uncertain significance
(Apr 28, 2017)
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criteria provided, single submitter
Method: clinical testing
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Usher syndrome type 1G
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001286824.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(Apr 07, 2020)
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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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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000065122.7
First in ClinVar: May 03, 2013 Last updated: Jul 03, 2020 |
Comment:
Variant classified as Uncertain Significance - Favor Benign. The p.Pro28Leu variant in USH1G has been reported in the heterozygous state in two individuals with Usher … (more)
Variant classified as Uncertain Significance - Favor Benign. The p.Pro28Leu variant in USH1G has been reported in the heterozygous state in two individuals with Usher syndrome type 2 (Aller 2007), one individual with retinitis pigmentosa (Haer-Wigman, 2017), and three children with apparently nonsyndromic hearing loss (LMM data). It has also been identified in 0.15% (138/91578) of Europeans chromosomes by gnomAD (http://gnomad.broadinstitute.org) and has been reported as likely benign by a clinical lab in ClinVar (Variation ID 48139). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, while the clinical significance of this variant is uncertain, its frequency suggests that it is more likely to be benign. ACMG/AMP Criteria applied: BS1_Supporting. (less)
Number of individuals with the variant: 4
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Likely benign
(May 12, 2020)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000970667.2
First in ClinVar: Aug 26, 2019 Last updated: Jul 15, 2021 |
Comment:
This variant is associated with the following publications: (PMID: 17896313, 28224992)
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Uncertain significance
(Jul 30, 2021)
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criteria provided, single submitter
Method: clinical testing
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Usher syndrome type 1G
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV002050132.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
Comment:
The USH1G c.83C>T; p.Pro28Leu variant (rs145448362) is reported in the literature in several individuals affected with Usher syndrome or retinitis pigmentosa, although a second variant … (more)
The USH1G c.83C>T; p.Pro28Leu variant (rs145448362) is reported in the literature in several individuals affected with Usher syndrome or retinitis pigmentosa, although a second variant was not reported in any individuals (Aller 2007, Haer-Wigman 2017, Le Quesne Stabej 2012). This variant is found in the non-Finnish European population with an overall allele frequency of 0.15% (138/91578 alleles) in the Genome Aggregation Database. The proline at codon 28 is highly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.353). Due to limited information, the clinical significance of the p.Pro28Leu variant is uncertain at this time. References: Aller et al. Screening of the USH1G gene among Spanish patients with Usher syndrome. Lack of mutations and evidence of a minor role in the pathogenesis of the syndrome. Ophthalmic Genet. 2007 Sep;28(3):151-5. PMID: 17896313. Haer-Wigman et al. Diagnostic exome sequencing in 266 Dutch patients with visual impairment. Eur J Hum Genet. 2017 May;25(5):591-599. PMID: 28224992. Le Quesne Stabej et al. Comprehensive sequence analysis of nine Usher syndrome genes in the UK National Collaborative Usher Study. J Med Genet. 2012 Jan;49(1):27-36. PMID: 22135276. (less)
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001975071.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001953701.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 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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Diagnostic exome sequencing in 266 Dutch patients with visual impairment. | Haer-Wigman L | European journal of human genetics : EJHG | 2017 | PMID: 28224992 |
Comprehensive sequence analysis of nine Usher syndrome genes in the UK National Collaborative Usher Study. | Le Quesne Stabej P | Journal of medical genetics | 2012 | PMID: 22135276 |
Screening of the USH1G gene among Spanish patients with Usher syndrome. Lack of mutations and evidence of a minor role in the pathogenesis of the syndrome. | Aller E | Ophthalmic genetics | 2007 | PMID: 17896313 |
Text-mined citations for rs145448362 ...
HelpRecord last updated Feb 04, 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.