ClinVar Genomic variation as it relates to human health
NM_206933.4(USH2A):c.6722C>T (p.Pro2241Leu)
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_206933.4(USH2A):c.6722C>T (p.Pro2241Leu)
Variation ID: 560523 Accession: VCV000560523.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q41 1: 215993103 (GRCh38) [ NCBI UCSC ] 1: 216166445 (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 Sep 10, 2018 Feb 14, 2024 Nov 4, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_206933.4:c.6722C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_996816.3:p.Pro2241Leu missense NC_000001.11:g.215993103G>A NC_000001.10:g.216166445G>A NG_009497.2:g.435346C>T - Protein change
- P2241L
- Other names
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- Canonical SPDI
- NC_000001.11:215993102: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), exomes 0.00000
- 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
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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USH2A | - | - |
GRCh38 GRCh37 |
6918 | 8387 |
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. |
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Likely pathogenic (2) |
criteria provided, single submitter
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Nov 4, 2023 | RCV000678653.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 13, 2023 | RCV001042036.6 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Apr 1, 2021 | RCV001724131.3 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Nov 4, 2023 | RCV002283505.3 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Nov 5, 2022 | RCV002469254.1 |
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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Likely pathogenic
(Apr 01, 2021)
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criteria provided, single submitter
Method: curation
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Retinitis pigmentosa
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001950405.1
First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
Comment:
The p.Pro2241Leu variant in USH2A was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics … (more)
The p.Pro2241Leu variant in USH2A was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PM2, PP3, PM3, PM1. Based on this evidence we have classified this variant as Likely Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab. (less)
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Likely pathogenic
(Sep 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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Retinitis pigmentosa 39
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002573090.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Same nucleotide change resulting in same amino … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000560523). Different missense changes at the same codon (p.Pro2241His, p.Pro2241Thr) have been reported to be associated with USH2A -related disorder (ClinVar ID: VCV000374001 / PMID: 27460420). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Retinal dystrophy (present) , Abnormal retinal morphology (present) , Visual loss (present)
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Likely pathogenic
(Nov 05, 2022)
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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: SCV002766559.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Variant summary: USH2A c.6722C>T (p.Pro2241Leu) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. … (more)
Variant summary: USH2A c.6722C>T (p.Pro2241Leu) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR003961) 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 4e-06 in 251092 control chromosomes (gnomAD). c.6722C>T has been reported in the literature as a biallelic genotype in individuals affected with Usher Syndrome (e.g. van Huet_2015, Hartel_2016, Pierrache_2016, Haer-Wigman_2017, Reurink_2021). 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. Four ClinVar submitters have assessed the variant since 2014: three classified the variant as likely pathogenic, and one as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Likely pathogenic
(Nov 04, 2023)
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criteria provided, single submitter
Method: clinical testing
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Usher syndrome type 2A
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV004181624.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
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Likely pathogenic
(Nov 04, 2023)
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criteria provided, single submitter
Method: clinical testing
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Retinitis pigmentosa 39
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV004181623.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
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Pathogenic
(Apr 09, 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: SCV004200748.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Oct 13, 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: SCV001205694.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 2241 of the USH2A protein (p.Pro2241Leu). … (more)
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 2241 of the USH2A protein (p.Pro2241Leu). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individuals with retinitis pigmentosa and/or Usher syndrome (PMID: 25999674, 26927203, 27318125, 28224992; Invitae). ClinVar contains an entry for this variant (Variation ID: 560523). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on USH2A protein function. This variant disrupts the p.Pro2241 amino acid residue in USH2A. Other variant(s) that disrupt this residue have been observed in individuals with USH2A-related conditions (PMID: 27460420), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Sep 01, 2016)
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no assertion criteria provided
Method: clinical testing
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Usher syndrome type 2A
Affected status: yes
Allele origin:
inherited,
unknown
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Accession: SCV000804744.2
First in ClinVar: Sep 10, 2018 Last updated: Sep 10, 2018 |
Observation 1:
Number of individuals with the variant: 1
Observation 2:
Number of individuals with the variant: 2
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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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The importance of automation in genetic diagnosis: Lessons from analyzing an inherited retinal degeneration cohort with the Mendelian Analysis Toolkit (MATK). | Zampaglione E | Genetics in medicine : official journal of the American College of Medical Genetics | 2022 | PMID: 34906470 |
Molecular Inversion Probe-Based Sequencing of USH2A Exons and Splice Sites as a Cost-Effective Screening Tool in USH2 and arRP Cases. | Reurink J | International journal of molecular sciences | 2021 | PMID: 34203967 |
Diagnostic exome sequencing in 266 Dutch patients with visual impairment. | Haer-Wigman L | European journal of human genetics : EJHG | 2017 | PMID: 28224992 |
An innovative strategy for the molecular diagnosis of Usher syndrome identifies causal biallelic mutations in 93% of European patients. | Bonnet C | European journal of human genetics : EJHG | 2016 | PMID: 27460420 |
A combination of two truncating mutations in USH2A causes more severe and progressive hearing impairment in Usher syndrome type IIa. | Hartel BP | Hearing research | 2016 | PMID: 27318125 |
Visual Prognosis in USH2A-Associated Retinitis Pigmentosa Is Worse for Patients with Usher Syndrome Type IIa Than for Those with Nonsyndromic Retinitis Pigmentosa. | Pierrache LH | Ophthalmology | 2016 | PMID: 26927203 |
The efficacy of microarray screening for autosomal recessive retinitis pigmentosa in routine clinical practice. | van Huet RA | Molecular vision | 2015 | PMID: 25999674 |
Text-mined citations for rs1057518826 ...
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.