ClinVar Genomic variation as it relates to human health
NM_206933.4(USH2A):c.4124C>T (p.Ser1375Leu)
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(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_206933.4(USH2A):c.4124C>T (p.Ser1375Leu)
Variation ID: 1056888 Accession: VCV001056888.12
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 1q41 1: 216196680 (GRCh38) [ NCBI UCSC ] 1: 216370022 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 13, 2021 Feb 20, 2024 Dec 12, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_206933.4:c.4124C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_996816.3:p.Ser1375Leu missense NM_007123.6:c.4124C>T NP_009054.6:p.Ser1375Leu missense NC_000001.11:g.216196680G>A NC_000001.10:g.216370022G>A NG_009497.2:g.231769C>T - Protein change
- S1375L
- Other names
- -
- Canonical SPDI
- NC_000001.11:216196679:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
-
Allele frequency
Help
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
Exome Aggregation Consortium (ExAC) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00003
- 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 | ||
---|---|---|---|---|---|---|
HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
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. |
|||
USH2A | - | - |
GRCh38 GRCh37 |
6918 | 8386 | |
USH2A-AS1 | - | - | - | GRCh38 | - | 721 |
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. |
---|---|---|---|---|
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Dec 12, 2023 | RCV001365783.9 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
|
Aug 14, 2023 | RCV001376389.3 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
Feb 17, 2023 | RCV003155401.1 |
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. |
|
---|---|---|---|---|---|
Uncertain significance
(Apr 08, 2021)
|
criteria provided, single submitter
Method: research
|
Retinitis pigmentosa 39
Affected status: yes
Allele origin:
germline
|
Ocular Genomics Institute, Massachusetts Eye and Ear
Accession: SCV001573510.1
First in ClinVar: May 10, 2021 Last updated: May 10, 2021 |
Comment:
The USH2A c.4124C>T 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.4124C>T 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. Based on this evidence we have classified this variant as Variant of Uncertain Significance. (less)
|
|
Likely pathogenic
(Feb 17, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Usher syndrome
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003844962.1
First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023 |
Comment:
Variant summary: USH2A c.4124C>T (p.Ser1375Leu) 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.4124C>T (p.Ser1375Leu) results in a non-conservative amino acid change located in the fibronectin type III domain (IPR003961) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250610 control chromosomes (gnomAD). c.4124C>T has been reported in the literature in the heterozygous state in an individual affected with Usher Syndrome and in the compound heterozygous state in at least three individuals affected with retinitis pigmentosa, including two siblings where the variant was confirmed to be in trans with a pathogenic variant (e.g. Zein_2015, Colombo_2018, Gao_2019, Gao_2021, Colombo_2022). These data indicate that the variant is likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either likely pathogenic (n=2) or VUS (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
|
|
Likely pathogenic
(Mar 13, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001789625.2
First in ClinVar: Aug 18, 2021 Last updated: Apr 01, 2023 |
Comment:
Observed with a second variant (phase unknown) in unrelated patients with retinitis pigmentosa in the published literature (Colombo et al., 2018; Gao et al., 2020); … (more)
Observed with a second variant (phase unknown) in unrelated patients with retinitis pigmentosa in the published literature (Colombo et al., 2018; Gao et al., 2020); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25425308, 29940899, 31054281, 34781295, 32188678) (less)
|
|
Likely pathogenic
(Aug 14, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Retinitis pigmentosa 39
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004208333.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
Pathogenic
(Dec 12, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV001562065.4
First in ClinVar: Apr 13, 2021 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 1375 of the USH2A protein (p.Ser1375Leu). … (more)
This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 1375 of the USH2A protein (p.Ser1375Leu). This variant is present in population databases (rs751479180, gnomAD 0.0009%). This missense change has been observed in individual(s) with retinitis pigmentosa (PMID: 25425308, 32188678, 34781295; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1056888). 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 USH2A protein function with a negative predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. (less)
|
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 |
---|---|---|---|---|
Spectral-Domain Optical Coherence Tomography Analysis in Syndromic and Nonsyndromic Forms of Retinitis Pigmentosa due to USH2A Genetic Variants. | Colombo L | Ophthalmic research | 2022 | PMID: 34781295 |
Prevalence and genetic-phenotypic characteristics of patients with USH2A mutations in a large cohort of Chinese patients with inherited retinal disease. | Gao FJ | The British journal of ophthalmology | 2021 | PMID: 32188678 |
Genetic and Clinical Findings in a Large Cohort of Chinese Patients with Suspected Retinitis Pigmentosa. | Gao FJ | Ophthalmology | 2019 | PMID: 31054281 |
Comparison of 5-year progression of retinitis pigmentosa involving the posterior pole among siblings by means of SD-OCT: a retrospective study. | Colombo L | BMC ophthalmology | 2018 | PMID: 29940899 |
Cone responses in Usher syndrome types 1 and 2 by microvolt electroretinography. | Zein WM | Investigative ophthalmology & visual science | 2014 | PMID: 25425308 |
Text-mined citations for rs751479180 ...
HelpRecord last updated Feb 28, 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.