NM_206933.4(USH2A):c.12295-3T>A AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jan 11, 2024
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:: RCV000414389.13

Allele description [Variation Report for NM_206933.4(USH2A):c.12295-3T>A]

NM_206933.4(USH2A):c.12295-3T>A

Gene:

USH2A:usherin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q41

Genomic location:

Preferred name:

NM_206933.4(USH2A):c.12295-3T>A

HGVS:

NC_000001.11:g.215675619A>T
NG_009497.2:g.752830T>A
NM_206933.4:c.12295-3T>AMANE SELECT
NC_000001.10:g.215848961A>T
NG_009497.1:g.752778T>A
NM_206933.2:c.12295-3T>A
NM_206933.3(USH2A):c.12295-3T>A
c.12295-3T>A

Links:

dbSNP: rs111033518

NCBI 1000 Genomes Browser:

rs111033518

Molecular consequence:

NM_206933.4:c.12295-3T>A - intron variant - [Sequence Ontology: SO:0001627]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

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regulator of G-protein signaling 10 [Rattus norvegicus]
regulator of G-protein signaling 10 [Rattus norvegicus]
gi|158749571|ref|NP_062210.1|

Protein
Oligocottus rubellio NADH dehydrogenase subunit 1 gene, partial cds; mitochondri...
Oligocottus rubellio NADH dehydrogenase subunit 1 gene, partial cds; mitochondrial
gi|155543542|gb|EF521356.1|

Nucleotide
Lhx6 protein [Mus musculus]
Lhx6 protein [Mus musculus]
gi|40787713|gb|AAH65077.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000231910	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Pathogenic (Apr 27, 2015)	germline	clinical testing	Citation Link,
SCV000490875	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Sep 13, 2021)	germline	clinical testing	Citation Link,
SCV001207341	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 11, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 22135276, 25910913, 17576681, 9536098, 25649381, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000231910

Eurofins Ntd Llc (ga)

criteria provided, single submitter

(EGL Classification Definitions 2015)

Pathogenic
(Apr 27, 2015)

germline

clinical testing

Citation Link,

SCV000490875

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Sep 13, 2021)

germline

clinical testing

Citation Link,

SCV001207341

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 11, 2024)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

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	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Comprehensive sequence analysis of nine Usher syndrome genes in the UK National Collaborative Usher Study.

Le Quesne Stabej P, Saihan Z, Rangesh N, Steele-Stallard HB, Ambrose J, Coffey A, Emmerson J, Haralambous E, Hughes Y, Steel KP, Luxon LM, Webster AR, Bitner-Glindzicz M.

J Med Genet. 2012 Jan;49(1):27-36. doi: 10.1136/jmedgenet-2011-100468. Epub 2011 Dec 1.

PubMed [citation]

PMID:: 22135276
PMCID:: PMC3678402

High Diagnostic Yield of Whole Exome Sequencing in Participants With Retinal Dystrophies in a Clinical Ophthalmology Setting.

Lee K, Berg JS, Milko L, Crooks K, Lu M, Bizon C, Owen P, Wilhelmsen KC, Weck KE, Evans JP, Garg S.

Am J Ophthalmol. 2015 Aug;160(2):354-363.e9. doi: 10.1016/j.ajo.2015.04.026. Epub 2015 Apr 22.

PubMed [citation]

PMID:: 25910913
PMCID:: PMC4506879

See all PubMed Citations (6)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000231910.5

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

#	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		1	not provided	not provided	not provided

From GeneDx, SCV000490875.4

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

Description

RNA functional studies of the c.12295-3T>A variant demonstrate out-of-frame skipping of exon 63 which leads to the expression of a smaller transcript and results in a premature termination codon (Lenassi et al., 2015); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 22135276, 25910913, 25649381)

#	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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001207341.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change falls in intron 62 of the USH2A gene. It does not directly change the encoded amino acid sequence of the USH2A protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs111033518, gnomAD 0.005%). This variant has been observed in individual(s) with clinical features of USH2A-related disease (PMID: 22135276, 25649381, 25910913). 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: 48395). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in exon 63 skipping and introduces a premature termination codon (PMID: 25649381). The resulting mRNA is expected to undergo nonsense-mediated decay. 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

Last Updated: Sep 29, 2024

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