VCV000048564.54 - ClinVar

NM_206933.4(USH2A):c.653T>A (p.Val218Glu)

Germline

Classification

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.

(16)

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.

Conflicting classifications of pathogenicity
Pathogenic(8); Likely pathogenic(1); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_206933.4(USH2A):c.653T>A (p.Val218Glu)

Variation ID: 48564 Accession: VCV000048564.54

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q41 1: 216365084 (GRCh38) [ NCBI UCSC ] 1: 216538426 (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	Dec 11, 2016	Oct 20, 2024	Dec 29, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_206933.4:c.653T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_996816.3:p.Val218Glu	missense
NM_007123.6:c.653T>A	NP_009054.6:p.Val218Glu	missense
NC_000001.11:g.216365084A>T
NC_000001.10:g.216538426A>T
NG_009497.2:g.63365T>A
	O75445:p.Val218Glu

... more HGVS ... less HGVS

Protein change

V218E

Other names

Canonical SPDI

NC_000001.11:216365083:A:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00002

Links

ClinGen: CA262114 UniProtKB: O75445#VAR_025762 dbSNP: rs397518026 VarSome

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
Gene	OMIM	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	7084	8579

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.
Rare genetic deafness	Pathogenic (1)	criteria provided, single submitter	Aug 9, 2016	RCV000041890.7
not provided	Conflicting interpretations of pathogenicity (7)	criteria provided, conflicting classifications	Dec 13, 2023	RCV000408647.43
Retinitis pigmentosa	Likely pathogenic (2)	criteria provided, single submitter	Apr 1, 2021	RCV000504825.5
Retinitis pigmentosa 39	Pathogenic (2)	criteria provided, single submitter	Dec 29, 2023	RCV000675152.4
Retinal dystrophy	Pathogenic (1)	criteria provided, single submitter	Nov 15, 2018	RCV001075204.3
Usher syndrome type 2A	Pathogenic (2)	criteria provided, single submitter	May 9, 2022	RCV001826599.4
USH2A-related disorder	Pathogenic (1)	no assertion criteria provided	Sep 5, 2024	RCV004537156.2

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.
Pathogenic (Nov 15, 2018)	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme) Method: clinical testing	Retinal dystrophy Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV001240818.1 First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 Comment: My Retina Tracker patient
Pathogenic (Dec 29, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Retinitis pigmentosa 39 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004207693.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Uncertain significance (Sep 24, 2015)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000484497.4 First in ClinVar: Dec 11, 2016 Last updated: Dec 11, 2016	Publications: PubMed (3) PubMed: 11311042‚ 17405132‚ 24498627 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=USH2A Number of individuals with the variant: 1 Sex: mixed
Pathogenic (Aug 09, 2016)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	Rare genetic deafness (Autosomal recessive inheritance) Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000065586.6 First in ClinVar: May 03, 2013 Last updated: Apr 09, 2018	Publications: PubMed (8) PubMed: 18281613‚ 11311042‚ 17405132‚ 20052763‚ 23591405‚ 24498627‚ 16963483‚ 21569298 Comment: The p.Val218Glu variant in USH2A has been reported in at least 8 individuals wit h Usher syndrome, all of whom carried a second, pathogenic USH2A … (more) The p.Val218Glu variant in USH2A has been reported in at least 8 individuals wit h Usher syndrome, all of whom carried a second, pathogenic USH2A variant on the other allele (Leroy 2001, Cremers 2007, Baux 2007, Herrera 2008, Bonnet 2011, Gl ockle 2013, Besnard 2014). This variant has also been identified in 5/66590 Euro pean chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadins titute.org; dbSNP rs397518026). Although it has been seen in the general populat ion, its frequency is low enough to be consistent with a recessive carrier frequ ency. In summary, this variant meets criteria to be classified as pathogenic for Usher syndrome in an autosomal recessive manner based upon its occurrence in tr ans with known pathogenic USH2A variants in multiple affected individuals. (less) Number of individuals with the variant: 3
Pathogenic (Oct 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001447913.1 First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020	Clinical Features: Rod-cone dystrophy (present) Sex: female
Likely pathogenic (Apr 01, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Retinitis pigmentosa (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Accession: SCV001950401.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021	Publications: PubMed (13) PubMed: 34906470‚ 11311042‚ 16963483‚ 17405132‚ 18281613‚ 20052763‚ 21569298‚ 23591405‚ 24498627‚ 24944099‚ 27460420‚ 28041643‚ 28559085 Comment: The p.Val218Glu 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.Val218Glu 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-S. 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)
Pathogenic (May 09, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Usher syndrome type 2A Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002579878.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PS4, PM3_STR, PM2_SUP, PP3	Number of individuals with the variant: 1 Sex: female
Pathogenic (Sep 27, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002577255.2 First in ClinVar: Oct 08, 2022 Last updated: Mar 04, 2023	Comment: 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; … (more) 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: 17405132, 18463160, 20052763, 16963483, 32531858, 11311042, 28944237, 27460420, 23591405, 21569298, 18281613, 27318125, 25902111, 26654877, 24498627, 28041643, 28559085, 24944099) (less)
Pathogenic (Dec 13, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000963510.6 First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 11311042‚ 16963483‚ 21569298‚ 28559085 Comment: This sequence change replaces valine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 218 of the USH2A protein … (more) This sequence change replaces valine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 218 of the USH2A protein (p.Val218Glu). This variant is present in population databases (rs397518026, gnomAD 0.007%). This missense change has been observed in individual(s) with Usher syndrome (PMID: 11311042, 16963483, 21569298, 28559085). 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: 48564). 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. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Jul 01, 2022)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001250066.26 First in ClinVar: May 09, 2020 Last updated: Oct 20, 2024	Comment: USH2A: PM3:Very Strong, PM2, PP4 Number of individuals with the variant: 7
Likely pathogenic (Jan 01, 2015)	no assertion criteria provided Method: research	Retinitis pigmentosa Affected status: yes Allele origin: unknown	NIHR Bioresource Rare Diseases, University of Cambridge Accession: SCV000598821.1 First in ClinVar: Sep 09, 2017 Last updated: Sep 09, 2017	Publications: PubMed (2) PubMed: 28041643‚ 11311042 Number of individuals with the variant: 1 Sex: female Ethnicity/Population group: NA
Pathogenic (Apr 20, 2017)	no assertion criteria provided Method: clinical testing	Retinitis pigmentosa 39 Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000800758.2 First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018	Publications: PubMed (4) PubMed: 27460420‚ 24944099‚ 23591405‚ 20052763
Likely pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001923955.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Likely pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	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: SCV001959678.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Pathogenic (Sep 29, 2021)	no assertion criteria provided Method: clinical testing	Usher syndrome type 2A Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002094022.1 First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022
Pathogenic (Sep 05, 2024)	no assertion criteria provided Method: clinical testing	USH2A-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004720609.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: The USH2A c.653T>A variant is predicted to result in the amino acid substitution p.Val218Glu. This variant has been reported in the compound heterozygous state with … (more) The USH2A c.653T>A variant is predicted to result in the amino acid substitution p.Val218Glu. This variant has been reported in the compound heterozygous state with a second pathogenic or likely pathogenic USH2A variant in multiple unrelated affected patients (Leroy et al. 2001. PubMed ID: 11311042; Baux et al. 2007. PubMed ID: 17405132; Cremers et al. 2007. PubMed ID: 16963483; Herrera et al. 2008. PubMed ID: 18281613; Besnard et al. 2014. PubMed ID: 24498627; Table S2, Bonnet et al. 2016. PubMed ID: 27460420; Table S2, Carss et al. 2016. PubMed ID: 28041643). This variant is reported in 0.0071% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. (less)
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Comment:

The p.Val218Glu variant in USH2A has been reported in at least 8 individuals wit h Usher syndrome, all of whom carried a second, pathogenic USH2A variant on the other allele (Leroy 2001, Cremers 2007, Baux 2007, Herrera 2008, Bonnet 2011, Gl ockle 2013, Besnard 2014). This variant has also been identified in 5/66590 Euro pean chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadins titute.org; dbSNP rs397518026). Although it has been seen in the general populat ion, its frequency is low enough to be consistent with a recessive carrier frequ ency. In summary, this variant meets criteria to be classified as pathogenic for Usher syndrome in an autosomal recessive manner based upon its occurrence in tr ans with known pathogenic USH2A variants in multiple affected individuals.

Comment:

The p.Val218Glu 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-S. 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.

Comment:

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: 17405132, 18463160, 20052763, 16963483, 32531858, 11311042, 28944237, 27460420, 23591405, 21569298, 18281613, 27318125, 25902111, 26654877, 24498627, 28041643, 28559085, 24944099)

Comment:

This sequence change replaces valine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 218 of the USH2A protein (p.Val218Glu). This variant is present in population databases (rs397518026, gnomAD 0.007%). This missense change has been observed in individual(s) with Usher syndrome (PMID: 11311042, 16963483, 21569298, 28559085). 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: 48564). 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. For these reasons, this variant has been classified as Pathogenic.

Comment:

The USH2A c.653T>A variant is predicted to result in the amino acid substitution p.Val218Glu. This variant has been reported in the compound heterozygous state with a second pathogenic or likely pathogenic USH2A variant in multiple unrelated affected patients (Leroy et al. 2001. PubMed ID: 11311042; Baux et al. 2007. PubMed ID: 17405132; Cremers et al. 2007. PubMed ID: 16963483; Herrera et al. 2008. PubMed ID: 18281613; Besnard et al. 2014. PubMed ID: 24498627; Table S2, Bonnet et al. 2016. PubMed ID: 27460420; Table S2, Carss et al. 2016. PubMed ID: 28041643). This variant is reported in 0.0071% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
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
Clinically Focused Molecular Investigation of 1000 Consecutive Families with Inherited Retinal Disease.	Stone EM	Ophthalmology	2017	PMID: 28559085
Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease.	Carss KJ	American journal of human genetics	2017	PMID: 28041643
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
Enrichment of LOVD-USHbases with 152 USH2A genotypes defines an extensive mutational spectrum and highlights missense hotspots.	Baux D	Human mutation	2014	PMID: 24944099
Experience of targeted Usher exome sequencing as a clinical test.	Besnard T	Molecular genetics & genomic medicine	2014	PMID: 24498627
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
Complete exon sequencing of all known Usher syndrome genes greatly improves molecular diagnosis.	Bonnet C	Orphanet journal of rare diseases	2011	PMID: 21569298
Ex vivo splicing assays of mutations at noncanonical positions of splice sites in USHER genes.	Le Guédard-Méreuze S	Human mutation	2010	PMID: 20052763
Retinal disease in Usher syndrome III caused by mutations in the clarin-1 gene.	Herrera W	Investigative ophthalmology & visual science	2008	PMID: 18281613
Molecular and in silico analyses of the full-length isoform of usherin identify new pathogenic alleles in Usher type II patients.	Baux D	Human mutation	2007	PMID: 17405132
Development of a genotyping microarray for Usher syndrome.	Cremers FP	Journal of medical genetics	2007	PMID: 16963483
Spectrum of mutations in USH2A in British patients with Usher syndrome type II.	Leroy BP	Experimental eye research	2001	PMID: 11311042
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=USH2A	-	-	-	-
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Text-mined citations for rs397518026 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_206933.4(USH2A):c.653T>A (p.Val218Glu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs397518026 ...