VCV000048374.33 - ClinVar

NM_206933.4(USH2A):c.11404G>A (p.Glu3802Lys)

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.

(10)

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.11404G>A (p.Glu3802Lys)

Variation ID: 48374 Accession: VCV000048374.33

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q41 1: 215743321 (GRCh38) [ NCBI UCSC ] 1: 215916663 (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	Aug 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_206933.4:c.11404G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_996816.3:p.Glu3802Lys	missense
NC_000001.11:g.215743321C>T
NC_000001.10:g.215916663C>T
NG_009497.2:g.685128G>A

Protein change

E3802K

Other names

Canonical SPDI

NC_000001.11:215743320: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.

0.00040 (T)

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

1000 Genomes Project 30x 0.00031

1000 Genomes Project 0.00040

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00146

The Genome Aggregation Database (gnomAD), exomes 0.00249

Exome Aggregation Consortium (ExAC) 0.00253

Links

ClinGen: CA143257 dbSNP: rs147900972 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	7071	8566

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 (4)	criteria provided, multiple submitters, no conflicts	May 10, 2022	RCV000041695.14
not provided	Benign/Likely benign (4)	criteria provided, multiple submitters, no conflicts	Aug 1, 2024	RCV000828963.24
Retinitis pigmentosa 39	Likely benign (1)	criteria provided, single submitter	Nov 4, 2023	RCV003450748.1
Usher syndrome type 2A	Likely benign (1)	criteria provided, single submitter	Nov 4, 2023	RCV003450747.1

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.
Benign (Aug 10, 2017)	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: SCV000065391.6 First in ClinVar: May 03, 2013 Last updated: Apr 09, 2018	Comment: p.Glu3802Lys in exon 59 of USH2A: This variant is not expected to have clinical significance because it has been identified in 1.3% (280/21974) of Finnish … (more) p.Glu3802Lys in exon 59 of USH2A: This variant is not expected to have clinical significance because it has been identified in 1.3% (280/21974) of Finnish chrom osomes including 2 homozygotes by the Genome Aggregation Database (gnomAD, http: //gnomad.broadinstitute.org; dbSNP rs147900972). In addition, computational anal yses do not suggest a high likelihood of clinical significance primarily based u pon a lack of conservation across species including mammals. Of note, orangutan, rat, mouse, dog and cow have a lysine at this position despite high nearby amin o acid conservation. (less) Number of individuals with the variant: 6
Benign (May 10, 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: SCV002547767.1 First in ClinVar: Jul 17, 2022 Last updated: Jul 17, 2022	Comment: Variant summary: USH2A c.11404G>A (p.Glu3802Lys) results in a conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. … (more) Variant summary: USH2A c.11404G>A (p.Glu3802Lys) results in a conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0025 in 249888 control chromosomes in the gnomAD database, including 3 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in USH2A causing Usher Syndrome (0.0025 vs 0.011), allowing no conclusion about variant significance. To our knowledge, no penetrant association of c.11404G>A in individuals affected with Usher Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three 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. 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: SCV001035637.6 First in ClinVar: Dec 17, 2019 Last updated: Feb 20, 2024
Likely benign (Aug 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: SCV004009934.12 First in ClinVar: Jul 16, 2023 Last updated: Oct 20, 2024	Comment: USH2A: BP4, BS2 Number of individuals with the variant: 6
Benign (Sep 03, 2019)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000970670.1 First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019	Comment: This variant is associated with the following publications: (PMID: 32707200)
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: SCV004182109.1 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: SCV004182110.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023
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: SCV001973500.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 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: SCV001923432.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified 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: SCV001955485.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021

Comment:

p.Glu3802Lys in exon 59 of USH2A: This variant is not expected to have clinical significance because it has been identified in 1.3% (280/21974) of Finnish chrom osomes including 2 homozygotes by the Genome Aggregation Database (gnomAD, http: //gnomad.broadinstitute.org; dbSNP rs147900972). In addition, computational anal yses do not suggest a high likelihood of clinical significance primarily based u pon a lack of conservation across species including mammals. Of note, orangutan, rat, mouse, dog and cow have a lysine at this position despite high nearby amin o acid conservation.

Comment:

Variant summary: USH2A c.11404G>A (p.Glu3802Lys) results in a conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0025 in 249888 control chromosomes in the gnomAD database, including 3 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in USH2A causing Usher Syndrome (0.0025 vs 0.011), allowing no conclusion about variant significance. To our knowledge, no penetrant association of c.11404G>A in individuals affected with Usher Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three 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. 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

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs147900972 ...

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 Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_206933.4(USH2A):c.11404G>A (p.Glu3802Lys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs147900972 ...