NM_206933.4(USH2A):c.7595-3C>G AND not provided

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Feb 9, 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:: RCV000178475.14

Allele description [Variation Report for NM_206933.4(USH2A):c.7595-3C>G]

NM_206933.4(USH2A):c.7595-3C>G

Gene:

USH2A:usherin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q41

Genomic location:

Preferred name:

NM_206933.4(USH2A):c.7595-3C>G

HGVS:

NC_000001.11:g.215889057G>C
NG_009497.2:g.539392C>G
NM_206933.4:c.7595-3C>GMANE SELECT
NC_000001.10:g.216062399G>C
NG_009497.1:g.539340C>G
NM_206933.2:c.7595-3C>G

Links:

dbSNP: rs201657446

NCBI 1000 Genomes Browser:

rs201657446

Molecular consequence:

NM_206933.4:c.7595-3C>G - intron variant - [Sequence Ontology: SO:0001627]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000230558	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Likely pathogenic (Jun 26, 2014)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 17405132, 20052763, 22135276, 24944099 Citation Link,
SCV001202174	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 19, 2024)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 17405132, 22135276, 24944099, 25097241, 26969326, 17576681, 9536098, 20052763, 28492532
SCV001811549	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Feb 9, 2024)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000230558

Eurofins Ntd Llc (ga)

criteria provided, single submitter

(EGL Classification Definitions 2015)

Likely pathogenic
(Jun 26, 2014)

germline

clinical testing

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

Citation Link,

SCV001202174

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 19, 2024)

germline

clinical testing

PubMed (9)
[See all records that cite these PMIDs]

SCV001811549

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Feb 9, 2024)

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	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Molecular and in silico analyses of the full-length isoform of usherin identify new pathogenic alleles in Usher type II patients.

Baux D, Larrieu L, Blanchet C, Hamel C, Ben Salah S, Vielle A, Gilbert-Dussardier B, Holder M, Calvas P, Philip N, Edery P, Bonneau D, Claustres M, Malcolm S, Roux AF.

Hum Mutat. 2007 Aug;28(8):781-9.

PubMed [citation]

PMID:: 17405132

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

See all PubMed Citations (9)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000230558.5

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

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001202174.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

This sequence change falls in intron 40 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 (rs201657446, gnomAD 0.002%). This variant has been observed in individual(s) with Usher syndrome type II (PMID: 17405132, 22135276, 24944099, 25097241, 26969326). 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: 197447). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 20052763). 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, SCV001811549.2

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

Description

Results in gain of a new acceptor splice site in intron 40; Published minigene assays demonstrate abnormal gene splicing with insertion of intronic sequence in the open reading frame, resulting in a frameshift and premature termination of translation (PMID: 20052763); Not observed at 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: 25649381, 24944099, 27208204, 34758253, 25097241, 22135276, 27460420, 20052763, 17405132, 26969326, 28981474, 28041643, 32176120, 32581362, 31589614, 36011334, 34948090, 31816670, 35266249, 31964843, 36819107)

#	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: Nov 24, 2024

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