VCV000048391.46 - ClinVar

NM_206933.4(USH2A):c.12093C>T (p.Tyr4031=)

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.

(12)

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.

Benign/Likely benign

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_206933.4(USH2A):c.12093C>T (p.Tyr4031=)

Variation ID: 48391 Accession: VCV000048391.46

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q41 1: 215680350 (GRCh38) [ NCBI UCSC ] 1: 215853692 (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	May 29, 2016	Sep 29, 2024	Jul 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_206933.4:c.12093C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_996816.3:p.Tyr4031=	synonymous
NC_000001.11:g.215680350G>A
NC_000001.10:g.215853692G>A
NG_009497.2:g.748099C>T

Protein change

Other names

p.Y4031Y:TAC>TAT

Canonical SPDI

NC_000001.11:215680349:G:A

Functional
consequence

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

Global minor allele
frequency (GMAF)

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.

0.00080 (A)

Allele frequency

The frequency of the allele represented by this VCV record.

1000 Genomes Project 30x 0.00078

1000 Genomes Project 0.00080

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00292

Exome Aggregation Consortium (ExAC) 0.00295

The Genome Aggregation Database (gnomAD) 0.00295

The Genome Aggregation Database (gnomAD), exomes 0.00304

Trans-Omics for Precision Medicine (TOPMed) 0.00315

Links

ClinGen: CA143281

dbSNP: rs55921307

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	7055	8544

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.
not specified	Benign/Likely benign (4)	criteria provided, multiple submitters, no conflicts	Feb 20, 2015	RCV000041713.14
not provided	Benign/Likely benign (5)	criteria provided, multiple submitters, no conflicts	Jul 1, 2024	RCV000949878.29
Usher syndrome type 2A	Likely benign (2)	criteria provided, single submitter	Nov 4, 2023	RCV001271127.3
Retinitis pigmentosa 39	Likely benign (1)	criteria provided, single submitter	Nov 4, 2023	RCV003450758.1

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.
Likely benign (Feb 20, 2015)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000231882.5 First in ClinVar: Jun 28, 2015 Last updated: May 03, 2018	Publications: PubMed (4) PubMed: 18273898‚ 19881469‚ 20507924‚ 22004887 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
Benign (Mar 20, 2012)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000065409.6 First in ClinVar: May 03, 2013 Last updated: May 03, 2018	Publications: PubMed (3) PubMed: 20507924‚ 18273898‚ 19881469 Comment: Tyr4031Tyr in exon 62 of USH2A: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, … (more) Tyr4031Tyr in exon 62 of USH2A: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located withi n the splice consensus sequence, has been identified in 0.46% (32/7020) of Europ ean American chromosomes and 0.08% (3/3738) of African American chromosomes in a broad population by the NHLBI Exome sequencing project (http://evs.gs.washingto n.edu/EVS/; dbSNP rs55921307) and has been reported in cases (5/651 (0.7%)) and controls (9/4482 (0.2%)) with statistically insignificant differences in frequen cy (Dreyer 2008, McGee 2010, Yan 2009). (less) Number of individuals with the variant: 20
Likely benign (Jul 01, 2024)	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: SCV001147665.25 First in ClinVar: Feb 03, 2020 Last updated: Aug 04, 2024	Comment: USH2A: BP4, BP7, BS2 Number of individuals with the variant: 14
Likely benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005261742.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Benign (May 02, 2012)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not specified Affected status: yes Allele origin: germline	GeneDx Accession: SCV000169766.10 First in ClinVar: Jun 23, 2014 Last updated: May 29, 2016	Comment: This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more) This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
Likely benign (Nov 04, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Retinitis pigmentosa 39 Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV004182041.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023
Likely benign (Nov 04, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Usher syndrome type 2A Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV004182042.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023
Benign (Feb 01, 2024)	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: SCV001096150.6 First in ClinVar: Dec 17, 2019 Last updated: Feb 20, 2024
Benign (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Usher syndrome type 2A Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001451978.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified 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: SCV001925387.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Likely benign (-)	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: SCV001959597.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001970048.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
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Comment:

Tyr4031Tyr in exon 62 of USH2A: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located withi n the splice consensus sequence, has been identified in 0.46% (32/7020) of Europ ean American chromosomes and 0.08% (3/3738) of African American chromosomes in a broad population by the NHLBI Exome sequencing project (http://evs.gs.washingto n.edu/EVS/; dbSNP rs55921307) and has been reported in cases (5/651 (0.7%)) and controls (9/4482 (0.2%)) with statistically insignificant differences in frequen cy (Dreyer 2008, McGee 2010, Yan 2009).

Comment:

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

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
Mutational screening of the USH2A gene in Spanish USH patients reveals 23 novel pathogenic mutations.	Garcia-Garcia G	Orphanet journal of rare diseases	2011	PMID: 22004887
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
Mutation analysis in the long isoform of USH2A in American patients with Usher Syndrome type II.	Yan D	Journal of human genetics	2009	PMID: 19881469
Spectrum of USH2A mutations in Scandinavian patients with Usher syndrome type II.	Dreyer B	Human mutation	2008	PMID: 18273898
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=USH2A	-	-	-	-

Text-mined citations for rs55921307 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_206933.4(USH2A):c.12093C>T (p.Tyr4031=)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs55921307 ...