NM_206933.4(USH2A):c.11389+3A>T AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Feb 6, 2025
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001386131.9

Allele description [Variation Report for NM_206933.4(USH2A):c.11389+3A>T]

NM_206933.4(USH2A):c.11389+3A>T

Gene:

USH2A:usherin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q41

Genomic location:

Preferred name:

NM_206933.4(USH2A):c.11389+3A>T

HGVS:

NC_000001.11:g.215758592T>A
NG_009497.2:g.669857A>T
NM_206933.4:c.11389+3A>TMANE SELECT
NC_000001.10:g.215931934T>A
NG_009497.1:g.669805A>T
NM_206933.2:c.11389+3A>T

Links:

dbSNP: rs753886165

NCBI 1000 Genomes Browser:

rs753886165

Molecular consequence:

NM_206933.4:c.11389+3A>T - intron variant - [Sequence Ontology: SO:0001627]

Functional consequence:

sequence_variant_affecting_splicing [Sequence Ontology: SO:1000071]

Condition(s)

Synonyms:: none provided; RECLASSIFIED - ADRA2C POLYMORPHISM; RECLASSIFIED - ADRB1 POLYMORPHISM
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001586256	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 19, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 28714225, 17576681, 9536098, 28492532
SCV002027980	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Feb 6, 2025)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001586256

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jul 19, 2022)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV002027980

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Feb 6, 2025)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Leveraging splice-affecting variant predictors and a minigene validation system to identify Mendelian disease-causing variants among exon-captured variants of uncertain significance.

Soens ZT, Branch J, Wu S, Yuan Z, Li Y, Li H, Wang K, Xu M, Rajan L, Motta FL, Simões RT, Lopez-Solache I, Ajlan R, Birch DG, Zhao P, Porto FB, Sallum J, Koenekoop RK, Sui R, Chen R.

Hum Mutat. 2017 Nov;38(11):1521-1533. doi: 10.1002/humu.23294. Epub 2017 Aug 18.

PubMed [citation]

PMID:: 28714225
PMCID:: PMC5638688

Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.

Buratti E, Chivers M, Královicová J, Romano M, Baralle M, Krainer AR, Vorechovsky I.

Nucleic Acids Res. 2007;35(13):4250-63. Epub 2007 Jun 18.

PubMed [citation]

PMID:: 17576681
PMCID:: PMC1934990

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001586256.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change falls in intron 58 of the USH2A gene. It does not directly change the encoded amino acid sequence of the USH2A protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs753886165, gnomAD 0.006%). This variant has been observed in individual(s) with Usher syndrome (PMID: 28714225; Invitae). 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: 427867). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneDx, SCV002027980.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

RNA studies demonstrate a damaging effect resulting in protein truncation and the skipping of exon 58 (PMID: 28714225); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 31045651, 31047384, 32093671, 33608557, 36110214, 34519870, 34906470, 32467589, 28714225, 35052368, 34148116, 35870892, 36819107, Li2022[paper], 38790200)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Apr 7, 2025

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