VCV000048427.62 - ClinVar

NM_206933.4(USH2A):c.14074G>A (p.Gly4692Arg)

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.

(13)

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

This variant is part of a Haplotype

NM_206933.2(USH2A):c.[12394del;14074G>A]

Identifiers

NM_206933.4(USH2A):c.14074G>A (p.Gly4692Arg)

Variation ID: 48427 Accession: VCV000048427.62

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q41 1: 215671031 (GRCh38) [ NCBI UCSC ] 1: 215844373 (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 9, 2018	Oct 20, 2024	Mar 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_206933.4:c.14074G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_996816.3:p.Gly4692Arg	missense
NC_000001.11:g.215671031C>T
NC_000001.10:g.215844373C>T
NG_009497.2:g.757418G>A
	O75445:p.Gly4692Arg

... more HGVS ... less HGVS

Protein change

G4692R

Other names

Canonical SPDI

NC_000001.11:215671030:C: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.

0.00220 (T)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 0.00220

1000 Genomes Project 30x 0.00234

Trans-Omics for Precision Medicine (TOPMed) 0.00404

The Genome Aggregation Database (gnomAD) 0.00419

The Genome Aggregation Database (gnomAD), exomes 0.00471

Exome Aggregation Consortium (ExAC) 0.00478

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00484

Links

ClinGen: CA143334 UniProtKB: O75445#VAR_061351 dbSNP: rs45549044 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	7080	8575

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 (3)	criteria provided, multiple submitters, no conflicts	Feb 26, 2022	RCV000041750.25
Retinitis pigmentosa 39 Usher syndrome type 2A	Likely benign (2)	criteria provided, multiple submitters, no conflicts	Aug 6, 2021	RCV000669410.10
not provided	Benign/Likely benign (6)	criteria provided, multiple submitters, no conflicts	Mar 1, 2024	RCV000756882.47
Usher syndrome type 2A	Likely benign (2)	criteria provided, single submitter	Jul 1, 2021	RCV001532872.12

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.
Benign (Sep 25, 2011)	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: SCV000065446.6 First in ClinVar: May 03, 2013 Last updated: Aug 26, 2019	Publications: PubMed (2) PubMed: 20507924‚ 19129697 Comment: Gly4692Ar in Exon 64 of USH2A: This variant is not expected to have clinical sig nificance because it has been identified in 0.6% (53/8600) of … (more) Gly4692Ar in Exon 64 of USH2A: This variant is not expected to have clinical sig nificance because it has been identified in 0.6% (53/8600) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/ EVS/; rs45549044). (less) Number of individuals with the variant: 17
Likely benign (May 20, 2019)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Athena Diagnostics Accession: SCV001146602.1 First in ClinVar: Jan 19, 2020 Last updated: Jan 19, 2020	Publications: PubMed (10) PubMed: 20507924‚ 22004887‚ 25333064‚ 26075083‚ 26927203‚ 22952768‚ 19129697‚ 25262649‚ 28224992‚ 29551606
Likely benign (Aug 06, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Usher syndrome type 2A Retinitis pigmentosa 39 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002807433.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Benign (Jul 24, 2018)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000515239.6 First in ClinVar: Mar 08, 2017 Last updated: Mar 04, 2023	Comment: This variant is associated with the following publications: (PMID: 22004887, 25333064, 25262649, 24944099, 26927203, 19129697, 30245029, 32707200)
Likely benign (Sep 19, 2017)	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018)) Method: clinical testing	Usher syndrome type 2A Retinitis pigmentosa 39 Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000794159.1 First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018	Publications: PubMed (9) PubMed: 26927203‚ 26075083‚ 25262649‚ 22004887‚ 28224992‚ 22952768‚ 25333064‚ 19129697‚ 20507924
Benign (Feb 09, 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: SCV000231928.5 First in ClinVar: Jun 28, 2015 Last updated: May 03, 2018	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: 4 Sex: mixed
Likely benign (Jul 01, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Usher syndrome type 2A Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV001748647.1 First in ClinVar: Jul 10, 2021 Last updated: Jul 10, 2021	Sex: mixed
Benign (Feb 26, 2022)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002104139.1 First in ClinVar: Mar 12, 2022 Last updated: Mar 12, 2022	Comment: Variant summary: USH2A c.14074G>A (p.Gly4692Arg) 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.14074G>A (p.Gly4692Arg) 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 0.0047 in 250890 control chromosomes in the gnomAD database, including 6 homozygotes. Although reported in the literature, to our knowledge, no penetrant association of c.14074G>A in individuals affected with Usher Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. (less)
Benign (Jan 31, 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: SCV001037459.5 First in ClinVar: Dec 17, 2019 Last updated: Feb 20, 2024
Benign (Nov 09, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000884848.6 First in ClinVar: Feb 18, 2019 Last updated: Feb 20, 2024
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: SCV005261737.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Likely benign (Mar 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: SCV001246240.26 First in ClinVar: May 09, 2020 Last updated: Oct 20, 2024	Comment: USH2A: BP4, BS2 Number of individuals with the variant: 13
Benign (Nov 08, 2019)	no assertion criteria provided Method: clinical testing	Usher syndrome type 2A Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002088237.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022
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Comment:

Gly4692Ar in Exon 64 of USH2A: This variant is not expected to have clinical sig nificance because it has been identified in 0.6% (53/8600) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/ EVS/; rs45549044).

Comment:

Variant summary: USH2A c.14074G>A (p.Gly4692Arg) 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 0.0047 in 250890 control chromosomes in the gnomAD database, including 6 homozygotes. Although reported in the literature, to our knowledge, no penetrant association of c.14074G>A in individuals affected with Usher Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.

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
SD-OCT imaging as a valuable tool to support molecular genetic diagnostics of Usher syndrome type 1.	Kremlikova Pourova R	Journal of AAPOS : the official publication of the American Association for Pediatric Ophthalmology and Strabismus	2018	PMID: 29551606
Diagnostic exome sequencing in 266 Dutch patients with visual impairment.	Haer-Wigman L	European journal of human genetics : EJHG	2017	PMID: 28224992
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
Choroidal Thickness Analysis in Patients with Usher Syndrome Type 2 Using EDI OCT.	Colombo L	Journal of ophthalmology	2015	PMID: 26075083
Screening for single nucleotide variants, small indels and exon deletions with a next-generation sequencing based gene panel approach for Usher syndrome.	Krawitz PM	Molecular genetics & genomic medicine	2014	PMID: 25333064
Utilizing ethnic-specific differences in minor allele frequency to recategorize reported pathogenic deafness variants.	Shearer AE	American journal of human genetics	2014	PMID: 25262649
Molecular diagnosis of Usher syndrome: application of two different next generation sequencing-based procedures.	Licastro D	PloS one	2012	PMID: 22952768
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
Audiometric characteristics of USH2a patients.	Leijendeckers JM	Audiology & neuro-otology	2009	PMID: 19129697
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=USH2A	-	-	-	-
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Text-mined citations for rs45549044 ...

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 10, 2024

ClinVar Genomic variation as it relates to human health

NM_206933.4(USH2A):c.14074G>A (p.Gly4692Arg)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs45549044 ...