VCV000228414.56 - ClinVar

NM_206933.4(USH2A):c.5776+1G>A

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.

(22)

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.

Pathogenic

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.5776+1G>A

Variation ID: 228414 Accession: VCV000228414.56

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q41 1: 216073096 (GRCh38) [ NCBI UCSC ] 1: 216246438 (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	Oct 20, 2024	Mar 17, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_206933.4:c.5776+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice donor
NC_000001.11:g.216073096C>T
NC_000001.10:g.216246438C>T
NG_009497.2:g.355353G>A

Protein change

Other names

p.p.(=)

Canonical SPDI

NC_000001.11:216073095: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.

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

The Genome Aggregation Database (gnomAD), exomes 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00000

Links

ClinGen: CA10576384 dbSNP: rs876657731 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
USH2A-AS2	-	-	-	GRCh38	-	560

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 provided	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Jan 19, 2024	RCV000255459.33
Rare genetic deafness	Pathogenic (1)	criteria provided, single submitter	Apr 2, 2015	RCV000213465.5
Retinitis pigmentosa 39 Usher syndrome type 2A	Pathogenic (1)	criteria provided, single submitter	Mar 22, 2022	RCV002500705.2
Autosomal recessive retinitis pigmentosa	Pathogenic (1)	no assertion criteria provided	Sep 10, 2015	RCV001257907.2
Retinal dystrophy	Pathogenic (1)	criteria provided, single submitter	Jul 23, 2019	RCV001074367.3
Usher syndrome type 2A	Pathogenic (6)	criteria provided, multiple submitters, no conflicts	Mar 17, 2024	RCV001002706.10
Usher syndrome	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Dec 15, 2023	RCV001375185.5
Usher syndrome type 2	Pathogenic (1)	no assertion criteria provided	Jun 23, 2019	RCV001003271.2
Retinitis pigmentosa 39	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Feb 13, 2024	RCV001542730.6
Retinitis pigmentosa	Pathogenic (1)	criteria provided, single submitter	Apr 1, 2021	RCV001723796.4

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 (Mar 17, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Usher syndrome type 2A Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004804949.2 First in ClinVar: Mar 30, 2024 Last updated: Apr 06, 2024
Pathogenic (Feb 01, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Usher syndrome type 2A Affected status: yes Allele origin: germline	Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals Accession: SCV001156362.1 First in ClinVar: Feb 16, 2020 Last updated: Feb 16, 2020	Number of individuals with the variant: 2 Clinical Features: Congenital sensorineural hearing impairment (present) , Myopia (present) , Nyctalopia (present) , Rod-cone dystrophy (present) Family history: yes
Pathogenic (Jul 23, 2019)	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme) Method: clinical testing	Retinal dystrophy Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV001239943.1 First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 Comment: My Retina Tracker patient
Pathogenic (Oct 01, 2021)	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: SCV001247003.26 First in ClinVar: May 09, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 3
Pathogenic (Apr 12, 2021)	criteria provided, single submitter (ClinGen HL ACMG Specifications v1) Method: clinical testing	Usher syndrome Affected status: yes Allele origin: germline	Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center Accession: SCV001571791.2 First in ClinVar: May 01, 2021 Last updated: May 01, 2021	Publications: PubMed (1) PubMed: 18273898 Comment: PVS1_Strong, PS1_Strong, PM2_Moderate, PM3_Supporting
Pathogenic (Jan 19, 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: SCV001590592.4 First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024	Publications: PubMed (8) PubMed: 16199547‚ 10729113‚ 10909849‚ 20507924‚ 25649381‚ 25097241‚ 26355662‚ 29490346 Comment: This sequence change affects a donor splice site in intron 28 of the USH2A gene. It is expected to disrupt RNA splicing. Variants that disrupt … (more) This sequence change affects a donor splice site in intron 28 of the USH2A gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in USH2A are known to be pathogenic (PMID: 10729113, 10909849, 20507924, 25649381). This variant is present in population databases (no rsID available, gnomAD 0.002%). Disruption of this splice site has been observed in individuals with Usher syndrome or retinitis pigmentosa (PMID: 25097241, 26355662, 29490346). ClinVar contains an entry for this variant (Variation ID: 228414). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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: SCV001950392.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021	Publications: PubMed (8) PubMed: 34906470‚ 18273898‚ 19683999‚ 25097241‚ 25558175‚ 25575603‚ 25649381‚ 18641288 Comment: The c.5776+1G>A 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 c.5776+1G>A 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: PVS1, PM2, PM3, PP3. Based on this evidence we have classified this variant as Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab. (less)
Pathogenic (Jan 03, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Usher syndrome type 2A Affected status: yes Allele origin: germline	3billion Accession: SCV002059192.1 First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022	Comment: Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are … (more) Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region (PVS1_VS).The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000228414). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000012, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Hearing impairment (present)
Pathogenic (Mar 23, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: yes Allele origin: germline	AiLife Diagnostics, AiLife Diagnostics Accession: SCV002502724.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022	Publications: PubMed (13) PubMed: 18273898‚ 31589614‚ 33576794‚ 29074561‚ 34426522‚ 29490346‚ 32552793‚ 32176120‚ 26355662‚ 31456290‚ 25097241‚ 25525159‚ 32037395 Number of individuals with the variant: 1 Secondary finding: yes
Pathogenic (Nov 08, 2021)	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2021)) Method: clinical testing	Usher syndrome type 2A Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV002060022.2 First in ClinVar: Jan 15, 2022 Last updated: Dec 24, 2022	Publications: PubMed (3) PubMed: 25575603‚ 25649381‚ 19683999 Comment: NM_206933.2(USH2A):c.5776+1G>A is a canonical splice variant classified as pathogenic in the context of USH2A-related disorders. c.5776+1G>A has been observed in cases with relevant disease (PMID: … (more) NM_206933.2(USH2A):c.5776+1G>A is a canonical splice variant classified as pathogenic in the context of USH2A-related disorders. c.5776+1G>A has been observed in cases with relevant disease (PMID: 25575603, 19683999). Functional assessments of this variant are available in the literature (PMID: 25649381). c.5776+1G>A has been observed in population frequency databases (gnomAD: NFE 0.002%). In summary, NM_206933.2(USH2A):c.5776+1G>A is a canonical splice variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. (less)
Pathogenic (Mar 22, 2022)	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: SCV002812875.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Apr 11, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Retinitis pigmentosa 39 Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV004172118.1 First in ClinVar: Dec 09, 2023 Last updated: Dec 09, 2023
Pathogenic (Apr 11, 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: SCV004172119.1 First in ClinVar: Dec 09, 2023 Last updated: Dec 09, 2023
Pathogenic (May 24, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV004238392.1 First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024
Pathogenic (Dec 15, 2023)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Usher syndrome Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV004241187.1 First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024	Publications: PubMed (2) PubMed: 23591405‚ 30459346 Comment: Variant summary: USH2A c.5776+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to … (more) Variant summary: USH2A c.5776+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing, showing the variant causes exon skipping resulting in a shortened mRNA product in a minigene assay (Fuster-Garcia_2018). The variant allele was found at a frequency of 1.2e-05 in 250072 control chromosomes. c.5776+1G>A has been reported in the literature in multiple individuals affected with Usher Syndrome, including as a homozygous phenotype (e.g. Fuster-Garcia_2018, Glockle_2014). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 30459346, 23591405). 16 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Feb 13, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Retinitis pigmentosa 39 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004208264.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (Apr 02, 2015)	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: SCV000271472.3 First in ClinVar: May 29, 2016 Last updated: May 29, 2016	Publications: PubMed (9) PubMed: 25575603‚ 25649381‚ 18641288‚ 25558175‚ 25097241‚ 24944099‚ 18273898‚ 23591405‚ 19683999 Comment: The c.5776+1G>A variant in USH2A has been previously reported in 12 individuals: 9 with Usher syndrome and 2 with retinitis pigmentosa (Baux 2014, Dreyer 2008, … (more) The c.5776+1G>A variant in USH2A has been previously reported in 12 individuals: 9 with Usher syndrome and 2 with retinitis pigmentosa (Baux 2014, Dreyer 2008, Glockle 2014, Jaijo 2010, Lenarduzzi 2015, Lenassi 2015, Sandberg 2008, Sodi 201 4, Wang 2014). Ten of these individuals were either compound heterozygous or hom ozygous for the variant. This variant has not been reported in large population studies. The c.5776+1G>A variant occurs in the invariant region (+/- 1/2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Furthermore, analysis of mRNA extracted from a c arrier of the c.5776+1G>A variant showed in-frame skipping of exon 28 (Lenassi 2 015), confirming a splicing impact. In summary, this variant meets our criteria to be classified as pathogenic for Usher syndrome in an autosomal recessive mann er (www.partners.org/personalizedmedicine/lmm) based upon its identification in the homozygous or compound heterozygous state in multiple affected individuals a nd the reported impact on splicing. (less) Number of individuals with the variant: 2
Pathogenic (Dec 14, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000321998.9 First in ClinVar: Oct 09, 2016 Last updated: Jan 21, 2023	Comment: Not observed at significant frequency in large population cohorts (gnomAD); Canonical splice site variant expected to result in aberrant splicing, although in the absence of … (more) Not observed at significant frequency in large population cohorts (gnomAD); Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 25525159, 26355662, 23591405, 29074561, 32531858, 25097241, 25649381, 34758253, 32188678, 31589614, 32552793, 32176120, 18273898, 24944099, 25558175, 25575603, 29490346, 19683999, 18641288, 31456290, 34426522, 33576794, 32037395, 34781295, 35266249) (less)
Pathogenic (Jun 23, 2019)	no assertion criteria provided Method: research	Usher syndrome type 2 Affected status: yes Allele origin: inherited	Sharon lab, Hadassah-Hebrew University Medical Center Accession: SCV001161354.1 First in ClinVar: Feb 16, 2020 Last updated: Feb 16, 2020
Pathogenic (Sep 10, 2015)	no assertion criteria provided Method: literature only	Autosomal recessive Retinitis Pigmentosa Affected status: yes Allele origin: germline	Faculty of Health Sciences, Beirut Arab University Accession: SCV001434723.1 First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020	Publications: PubMed (1) PubMed: 26355662 Number of individuals with the variant: 1 Ethnicity/Population group: Arab
Pathogenic (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Usher syndrome type 2A Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001462252.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
Likely pathogenic (-)	no assertion criteria provided (ACGS Guidelines, 2016) Method: clinical testing	Retinitis pigmentosa 39 Affected status: yes Allele origin: germline	Genomics England Pilot Project, Genomics England Accession: SCV001760017.1 First in ClinVar: Jul 31, 2021 Last updated: Jul 31, 2021
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Comment:

This sequence change affects a donor splice site in intron 28 of the USH2A gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in USH2A are known to be pathogenic (PMID: 10729113, 10909849, 20507924, 25649381). This variant is present in population databases (no rsID available, gnomAD 0.002%). Disruption of this splice site has been observed in individuals with Usher syndrome or retinitis pigmentosa (PMID: 25097241, 26355662, 29490346). ClinVar contains an entry for this variant (Variation ID: 228414). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

Comment:

The c.5776+1G>A 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: PVS1, PM2, PM3, PP3. Based on this evidence we have classified this variant as Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab.

Comment:

Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region (PVS1_VS).The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000228414). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000012, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

NM_206933.2(USH2A):c.5776+1G>A is a canonical splice variant classified as pathogenic in the context of USH2A-related disorders. c.5776+1G>A has been observed in cases with relevant disease (PMID: 25575603, 19683999). Functional assessments of this variant are available in the literature (PMID: 25649381). c.5776+1G>A has been observed in population frequency databases (gnomAD: NFE 0.002%). In summary, NM_206933.2(USH2A):c.5776+1G>A is a canonical splice variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

Comment:

Variant summary: USH2A c.5776+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing, showing the variant causes exon skipping resulting in a shortened mRNA product in a minigene assay (Fuster-Garcia_2018). The variant allele was found at a frequency of 1.2e-05 in 250072 control chromosomes. c.5776+1G>A has been reported in the literature in multiple individuals affected with Usher Syndrome, including as a homozygous phenotype (e.g. Fuster-Garcia_2018, Glockle_2014). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 30459346, 23591405). 16 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

The c.5776+1G>A variant in USH2A has been previously reported in 12 individuals: 9 with Usher syndrome and 2 with retinitis pigmentosa (Baux 2014, Dreyer 2008, Glockle 2014, Jaijo 2010, Lenarduzzi 2015, Lenassi 2015, Sandberg 2008, Sodi 201 4, Wang 2014). Ten of these individuals were either compound heterozygous or hom ozygous for the variant. This variant has not been reported in large population studies. The c.5776+1G>A variant occurs in the invariant region (+/- 1/2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Furthermore, analysis of mRNA extracted from a c arrier of the c.5776+1G>A variant showed in-frame skipping of exon 28 (Lenassi 2 015), confirming a splicing impact. In summary, this variant meets our criteria to be classified as pathogenic for Usher syndrome in an autosomal recessive mann er (www.partners.org/personalizedmedicine/lmm) based upon its identification in the homozygous or compound heterozygous state in multiple affected individuals a nd the reported impact on splicing.

Comment:

Not observed at significant frequency in large population cohorts (gnomAD); Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 25525159, 26355662, 23591405, 29074561, 32531858, 25097241, 25649381, 34758253, 32188678, 31589614, 32552793, 32176120, 18273898, 24944099, 25558175, 25575603, 29490346, 19683999, 18641288, 31456290, 34426522, 33576794, 32037395, 34781295, 35266249)

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
The genetic structure of the Turkish population reveals high levels of variation and admixture.	Kars ME	Proceedings of the National Academy of Sciences of the United States of America	2021	PMID: 34426522
Molecular Epidemiology in 591 Italian Probands With Nonsyndromic Retinitis Pigmentosa and Usher Syndrome.	Colombo L	Investigative ophthalmology & visual science	2021	PMID: 33576794
Analysis of transcript-deleterious variants in Mendelian disorders: implications for RNA-based diagnostics.	Maddirevula S	Genome biology	2020	PMID: 32552793
Establishing Genotype-phenotype Correlation in USH2A-related Disorders to Personalize Audiological Surveillance and Rehabilitation.	Molina-Ramírez LP	Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology	2020	PMID: 32176120
Copy-number variation contributes 9% of pathogenicity in the inherited retinal degenerations.	Zampaglione E	Genetics in medicine : official journal of the American College of Medical Genetics	2020	PMID: 32037395
A nationwide genetic analysis of inherited retinal diseases in Israel as assessed by the Israeli inherited retinal disease consortium (IIRDC).	Sharon D	Human mutation	2020	PMID: 31456290
Optimizing clinical exome design and parallel gene-testing for recessive genetic conditions in preconception carrier screening: Translational research genomic data from 14,125 exomes.	Capalbo A	PLoS genetics	2019	PMID: 31589614
High-throughput sequencing for the molecular diagnosis of Usher syndrome reveals 42 novel mutations and consolidates CEP250 as Usher-like disease causative.	Fuster-García C	Scientific reports	2018	PMID: 30459346
The Genetics of Usher Syndrome in the Israeli and Palestinian Populations.	Khalaileh A	Investigative ophthalmology & visual science	2018	PMID: 29490346
Assessment of the incorporation of CNV surveillance into gene panel next-generation sequencing testing for inherited retinal diseases.	Ellingford JM	Journal of medical genetics	2018	PMID: 29074561
Expanding the clinical, allelic, and locus heterogeneity of retinal dystrophies.	Patel N	Genetics in medicine : official journal of the American College of Medical Genetics	2016	PMID: 26355662
A detailed clinical and molecular survey of subjects with nonsyndromic USH2A retinopathy reveals an allelic hierarchy of disease-causing variants.	Lenassi E	European journal of human genetics : EJHG	2015	PMID: 25649381
Usher syndrome: an effective sequencing approach to establish a genetic and clinical diagnosis.	Lenarduzzi S	Hearing research	2015	PMID: 25575603
RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease.	Xiong HY	Science (New York, N.Y.)	2015	PMID: 25525159
MYO7A and USH2A gene sequence variants in Italian patients with Usher syndrome.	Sodi A	Molecular vision	2014	PMID: 25558175
Dependable and efficient clinical utility of target capture-based deep sequencing in molecular diagnosis of retinitis pigmentosa.	Wang J	Investigative ophthalmology & visual science	2014	PMID: 25097241
Enrichment of LOVD-USHbases with 152 USH2A genotypes defines an extensive mutational spectrum and highlights missense hotspots.	Baux D	Human mutation	2014	PMID: 24944099
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
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
Microarray-based mutation analysis of 183 Spanish families with Usher syndrome.	Jaijo T	Investigative ophthalmology & visual science	2010	PMID: 19683999
Disease course in patients with autosomal recessive retinitis pigmentosa due to the USH2A gene.	Sandberg MA	Investigative ophthalmology & visual science	2008	PMID: 18641288
Spectrum of USH2A mutations in Scandinavian patients with Usher syndrome type II.	Dreyer B	Human mutation	2008	PMID: 18273898
Splicing in action: assessing disease causing sequence changes.	Baralle D	Journal of medical genetics	2005	PMID: 16199547
Identification of novel USH2A mutations: implications for the structure of USH2A protein.	Dreyer B	European journal of human genetics : EJHG	2000	PMID: 10909849
Genomic structure and identification of novel mutations in usherin, the gene responsible for Usher syndrome type IIa.	Weston MD	American journal of human genetics	2000	PMID: 10729113
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Text-mined citations for rs876657731 ...

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.5776+1G>A

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs876657731 ...