ClinVar Genomic variation as it relates to human health
NM_206933.4(USH2A):c.7068T>G (p.Asn2356Lys)
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); Benign(4)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_206933.4(USH2A):c.7068T>G (p.Asn2356Lys)
Variation ID: 48576 Accession: VCV000048576.27
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q41 1: 215965369 (GRCh38) [ NCBI UCSC ] 1: 216138711 (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 May 25, 2017 May 12, 2024 Jan 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_206933.4:c.7068T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_996816.3:p.Asn2356Lys missense NC_000001.11:g.215965369A>C NC_000001.10:g.216138711A>C NG_009497.2:g.463080T>G - Protein change
- N2356K
- Other names
- -
- Canonical SPDI
- NC_000001.11:215965368:A:C
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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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0.00160 (C)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00051
Trans-Omics for Precision Medicine (TOPMed) 0.00056
Exome Aggregation Consortium (ExAC) 0.00078
The Genome Aggregation Database (gnomAD), exomes 0.00078
1000 Genomes Project 30x 0.00156
1000 Genomes Project 0.00160
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
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. |
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USH2A | - | - |
GRCh38 GRCh37 |
6944 | 8419 |
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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Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Mar 5, 2022 | RCV000041902.7 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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May 28, 2019 | RCV000490376.3 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 20, 2017 | RCV000671627.1 | |
Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Jan 31, 2024 | RCV000924303.21 |
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
(May 28, 2019)
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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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Mendelics
Accession: SCV001135546.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Benign
(Feb 28, 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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV003800109.2
First in ClinVar: Feb 13, 2023 Last updated: Mar 04, 2023 |
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Uncertain significance
(Mar 18, 2016)
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criteria provided, single submitter
Method: reference population
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Usher syndrome type 2A
Affected status: unknown
Allele origin:
germline
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Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center
Accession: SCV000267556.1
First in ClinVar: May 25, 2017 Last updated: May 25, 2017 |
Number of individuals with the variant: 2
Age: 40-69 years
Ethnicity/Population group: East Asian
Geographic origin: South Korean
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Uncertain significance
(Mar 05, 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: SCV002500134.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Comment:
Variant summary: USH2A c.7068T>G (p.Asn2356Lys) 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.7068T>G (p.Asn2356Lys) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR003961) 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 0.001 in 291028 control chromosomes, predominantly at a frequency of 0.01 within the East Asian subpopulation in the gnomAD database and has also been reported as a common variant in the Japanese normal hearing population (example, Moteki_2016). This frequency is close to or almost similar (i.e., not significantly lower) than estimated for a pathogenic variant in USH2A causing Usher Syndrome (0.01 in East Asian cohorts vs 0.011), supporting a benign outcome. In a cross sectional ascertainment spanning 2013-2021, c.7068T>G has been reported in the literature as a VUS and/or non-informative genotype in settings of multigene panel testing predominantly among East Asian cohorts of individuals with a variety of Usher syndrome related manifestations such as hearing loss (example, Miyagawa_2013), sporadic retinal dystrophy (example, Glockle_2014), Inherited Retinal Degeneration cohort (example, Huang_2015), Japanese Normal Hearing cohort (Moteki_2016), Usher syndrome cohort (example, Galli-Resta_2018, Meng_2021), an individual with Usher syndrome compound heterozygous for causative variants in the MYO7A gene (example, Li_2019), possible digenic association proposed in an individual with Inherited Retinal Degeneration (example, Liu_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Usher Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign/likely benign, n=3; VUS, n=4). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. (less)
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Uncertain significance
(Mar 31, 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: SCV001981926.4
First in ClinVar: Oct 30, 2021 Last updated: Aug 18, 2023 |
Comment:
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: 30073356, … (more)
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: 30073356, 30245029, 23591405, 25356976, 24938718, 25078356, 24853665, 23967202, 26346818, 29625443, 30804660, 32090030, 33105608, 34426522, 33691693, 33090715, 33124170, 35114279, 35860547, 32188678, 32675063, 35836572, 30826590) (less)
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Uncertain significance
(Dec 20, 2017)
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criteria provided, single submitter
Method: clinical testing
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Usher syndrome type 2A
Retinitis pigmentosa 39
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000796617.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
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Benign
(Sep 04, 2017)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000065598.6
First in ClinVar: May 03, 2013 Last updated: Apr 09, 2018 |
Number of individuals with the variant: 2
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Benign
(Jan 31, 2024)
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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: SCV001069814.6
First in ClinVar: Dec 17, 2019 Last updated: Feb 14, 2024 |
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Benign
(Feb 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004125612.5
First in ClinVar: Nov 20, 2023 Last updated: May 12, 2024 |
Comment:
USH2A: BP4, BS1, BS2
Number of individuals with the variant: 1
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Likely benign
(Apr 03, 2020)
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no assertion criteria provided
Method: clinical testing
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Usher syndrome type 2A
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001466773.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 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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Correlation between Genotype and Phenotype in 69 Chinese Patients with USH2A Mutations: A comparative study of the patients with Usher Syndrome and Nonsyndromic Retinitis Pigmentosa. | Meng X | Acta ophthalmologica | 2021 | PMID: 33124170 |
Simultaneous expression of two pathogenic genes in four Chinese patients affected with inherited retinal dystrophy. | Liu XZ | International journal of ophthalmology | 2020 | PMID: 32090030 |
Identification of four novel mutations in MYO7A gene and their association with nonsyndromic deafness and Usher Syndrome 1B. | Li Y | International journal of pediatric otorhinolaryngology | 2019 | PMID: 30826590 |
Central Retina Functional Damage in Usher Syndrome Type 2: 22 Years of Focal Macular ERG Analysis in a Patient Population From Central and Southern Italy. | Galli-Resta L | Investigative ophthalmology & visual science | 2018 | PMID: 30073356 |
Comprehensive genetic testing with ethnic-specific filtering by allele frequency in a Japanese hearing-loss population. | Moteki H | Clinical genetics | 2016 | PMID: 26346818 |
Genotype-phenotype correlation and mutation spectrum in a large cohort of patients with inherited retinal dystrophy revealed by next-generation sequencing. | Huang XF | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25356976 |
Genetic testing for sporadic hearing loss using targeted massively parallel sequencing identifies 10 novel mutations. | Gu X | Clinical genetics | 2015 | PMID: 24853665 |
Mutations of 60 known causative genes in 157 families with retinitis pigmentosa based on exome sequencing. | Xu Y | Human genetics | 2014 | PMID: 24938718 |
Panel-based next generation sequencing as a reliable and efficient technique to detect mutations in unselected patients with retinal dystrophies. | Glöckle N | European journal of human genetics : EJHG | 2014 | PMID: 23591405 |
Targeted exon sequencing successfully discovers rare causative genes and clarifies the molecular epidemiology of Japanese deafness patients. | Miyagawa M | PloS one | 2013 | PMID: 23967202 |
Text-mined citations for rs200038092 ...
HelpRecord last updated May 12, 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.