ClinVar Genomic variation as it relates to human health
NM_206933.4(USH2A):c.1550G>C (p.Arg517Thr)
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.
Pathogenic(1); Likely pathogenic(3); Uncertain significance(3)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_206933.4(USH2A):c.1550G>C (p.Arg517Thr)
Variation ID: 552769 Accession: VCV000552769.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q41 1: 216323474 (GRCh38) [ NCBI UCSC ] 1: 216496816 (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 Aug 5, 2018 Feb 14, 2024 Nov 5, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_206933.4:c.1550G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_996816.3:p.Arg517Thr missense NM_007123.6:c.1550G>C NP_009054.6:p.Arg517Thr missense NC_000001.11:g.216323474C>G NC_000001.10:g.216496816C>G NG_009497.2:g.104975G>C - Protein change
- R517T
- Other names
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- Canonical SPDI
- NC_000001.11:216323473:C:G
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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), exomes 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
- Links
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
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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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USH2A | - | - |
GRCh38 GRCh37 |
6920 | 8391 |
Conditions - Germline
Condition
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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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Uncertain significance (1) |
criteria provided, single submitter
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Jan 4, 2018 | RCV001075316.8 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Nov 5, 2023 | RCV001230842.15 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Sep 27, 2023 | RCV001376349.10 | |
Uncertain significance (1) |
criteria provided, single submitter
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Nov 16, 2021 | RCV001810471.10 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jul 26, 2023 | RCV001797777.8 |
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
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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 04, 2018)
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criteria provided, single submitter
Method: clinical testing
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Retinal dystrophy
Affected status: yes
Allele origin:
germline
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Blueprint Genetics
Accession: SCV001240934.1
First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 |
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Uncertain significance
(Apr 08, 2021)
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criteria provided, single submitter
Method: research
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Retinitis pigmentosa 39
Affected status: yes
Allele origin:
germline
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Ocular Genomics Institute, Massachusetts Eye and Ear
Accession: SCV001573465.1
First in ClinVar: May 10, 2021 Last updated: May 10, 2021 |
Comment:
The USH2A c.1550G>C variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we … (more)
The USH2A c.1550G>C variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2, PP3. Based on this evidence we have classified this variant as Variant of Uncertain Significance. (less)
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Uncertain significance
(Nov 16, 2021)
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criteria provided, single submitter
Method: clinical testing
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Usher syndrome type 2A
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV002060225.2
First in ClinVar: Jan 15, 2022 Last updated: Nov 29, 2022 |
Comment:
NM_206933.2(USH2A):c.1550G>C(R517T) is a missense variant classified as a variant of uncertain significance in the context of USH2A-related disorders. R517T has been observed in cases with … (more)
NM_206933.2(USH2A):c.1550G>C(R517T) is a missense variant classified as a variant of uncertain significance in the context of USH2A-related disorders. R517T has been observed in cases with relevant disease (PMID: 15671307, 15325563). Functional assessments of this variant are not available in the literature. R517T has been observed in population frequency databases (gnomAD: NFE <0.001%). In summary, there is insufficient evidence to classify NM_206933.2(USH2A):c.1550G>C(R517T) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. (less)
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Likely pathogenic
(Jul 26, 2023)
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criteria provided, single submitter
Method: clinical testing
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Usher syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002041850.2
First in ClinVar: Dec 25, 2021 Last updated: Aug 26, 2023 |
Comment:
Variant summary: USH2A c.1550G>C (p.Arg517Thr) results in a non-conservative amino acid change located in the Laminin, N-terminal domain (IPR008211) of the encoded protein sequence. Four … (more)
Variant summary: USH2A c.1550G>C (p.Arg517Thr) results in a non-conservative amino acid change located in the Laminin, N-terminal domain (IPR008211) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. In addition, this variant disrupts the last nucleotide of exon 8, and therefore can affect splicing. Computational tools predict no significant impact on normal splicing. However, this precludes an exact estimation of the computational splicing impact. The variant allele was found at a frequency of 4e-06 in 250598 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1550G>C has been reported in the literature in multiple individuals affected with Usher Syndrome and inherited retinal degeneration, including three homozygotes (two in one family) (e.g., Seyedahmadi_2004, Schwartz_2005, Zampaglione_2020). These data indicate that the variant is likely to be associated with disease. 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: 16963483, 20507924, 15671307, 15325563, 32037395). Five ClinVar submitters (evaluation after 2014) have reported the variant with conflicting interpretations: four submitters classified the variant as uncertain significance, and one submitter classified it as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Likely pathogenic
(Sep 26, 2023)
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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: SCV001812315.2
First in ClinVar: Sep 08, 2021 Last updated: Oct 05, 2023 |
Comment:
Last nucleotide of the exon variant in a gene for which loss of function is a known mechanism of disease, and both splice predictors and … (more)
Last nucleotide of the exon variant in a gene for which loss of function is a known mechanism of disease, and both splice predictors and evolutionary conservation support a deleterious effect, although in the absence of functional evidence the actual effect of this sequence change is unknown; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25525159, 20507924, 15325563, 15671307, 32037395) (less)
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Likely pathogenic
(Sep 27, 2023)
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criteria provided, single submitter
Method: clinical testing
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Retinitis pigmentosa 39
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004208234.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Nov 05, 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: SCV001403340.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 517 of the USH2A protein (p.Arg517Thr). … (more)
This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 517 of the USH2A protein (p.Arg517Thr). This variant also falls at the last nucleotide of exon 8, which is part of the consensus splice site for this exon. This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed in individuals with Usher syndrome or non-syndromic retinal disease (PMID: 15325563, 15671307, 20507924; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 552769). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (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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Copy-number variation contributes 9% of pathogenicity in the inherited retinal degenerations. | Zampaglione E | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 32037395 |
RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease. | Xiong HY | Science (New York, N.Y.) | 2015 | PMID: 25525159 |
Novel mutations in the long isoform of the USH2A gene in patients with Usher syndrome type II or non-syndromic retinitis pigmentosa. | McGee TL | Journal of medical genetics | 2010 | PMID: 20507924 |
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
Development of a genotyping microarray for Usher syndrome. | Cremers FP | Journal of medical genetics | 2007 | PMID: 16963483 |
Disease expression in Usher syndrome caused by VLGR1 gene mutation (USH2C) and comparison with USH2A phenotype. | Schwartz SB | Investigative ophthalmology & visual science | 2005 | PMID: 15671307 |
Comprehensive screening of the USH2A gene in Usher syndrome type II and non-syndromic recessive retinitis pigmentosa. | Seyedahmadi BJ | Experimental eye research | 2004 | PMID: 15325563 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
Text-mined citations for rs1393503590 ...
HelpRecord last updated Mar 23, 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.