NM_206933.4(USH2A):c.2802T>G (p.Cys934Trp) AND Retinitis pigmentosa 39

Germline classification:: Conflicting interpretations of pathogenicity (5 submissions)
Last evaluated:: Mar 27, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000576637.11

Allele description [Variation Report for NM_206933.4(USH2A):c.2802T>G (p.Cys934Trp)]

NM_206933.4(USH2A):c.2802T>G (p.Cys934Trp)

Genes:

LOC122152296:Sharpr-MPRA regulatory region 8762 [Gene]
USH2A:usherin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q41

Genomic location:

Preferred name:

NM_206933.4(USH2A):c.2802T>G (p.Cys934Trp)

HGVS:

NC_000001.11:g.216246592A>C
NG_009497.2:g.181857T>G
NG_076570.2:g.210A>C
NM_007123.6:c.2802T>G
NM_206933.4:c.2802T>GMANE SELECT
NP_009054.5:p.Cys934Trp
NP_009054.6:p.Cys934Trp
NP_996816.2:p.Cys934Trp
NP_996816.3:p.Cys934Trp
NC_000001.10:g.216419934A>C
NM_007123.5:c.2802T>G
NM_206933.2:c.2802T>G
NM_206933.3:c.2802T>G
O75445:p.Cys934Trp

Protein change:

C934W; CYS934TRP

Links:

UniProtKB: O75445#VAR_072000; OMIM: 608400.0016; dbSNP: rs201527662

NCBI 1000 Genomes Browser:

rs201527662

Molecular consequence:

NM_007123.6:c.2802T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_206933.4:c.2802T>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Retinitis pigmentosa 39 (RP39)
Identifiers:: MONDO: MONDO:0013436; MedGen: C3151138; Orphanet: 791; OMIM: 613809

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000678095	Counsyl	no assertion criteria provided	Likely pathogenic (Jan 13, 2017)	unknown	clinical testing	PubMed (5) [See all records that cite these PMIDs] 25324289, 26338283, 24938718, 27460420, 26310143
SCV001821765	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jul 22, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003841031	OMIM	no assertion criteria provided	Pathogenic (Apr 17, 2023)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV003922396	Pangenia Genomics, Pangenia Inc.	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 18, 2021)	unknown	research	PubMed (1) [See all records that cite this PMID]
SCV004207714	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 27, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
Asian	unknown	no	1	not provided	not provided	not provided	not provided	research
Asian	unknown	yes	1	not provided	not provided	not provided	not provided	research

Citations

PubMed

Comprehensive molecular diagnosis of a large cohort of Japanese retinitis pigmentosa and Usher syndrome patients by next-generation sequencing.

Oishi M, Oishi A, Gotoh N, Ogino K, Higasa K, Iida K, Makiyama Y, Morooka S, Matsuda F, Yoshimura N.

Invest Ophthalmol Vis Sci. 2014 Oct 16;55(11):7369-75. doi: 10.1167/iovs.14-15458.

PubMed [citation]

PMID:: 25324289

Comprehensive molecular diagnosis of 67 Chinese Usher syndrome probands: high rate of ethnicity specific mutations in Chinese USH patients.

Jiang L, Liang X, Li Y, Wang J, Zaneveld JE, Wang H, Xu S, Wang K, Wang B, Chen R, Sui R.

Orphanet J Rare Dis. 2015 Sep 4;10:110. doi: 10.1186/s13023-015-0329-3.

PubMed [citation]

PMID:: 26338283
PMCID:: PMC4559966

See all PubMed Citations (7)

Details of each submission

From Counsyl, SCV000678095.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

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

From Genome-Nilou Lab, SCV001821765.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From OMIM, SCV003841031.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In 5 Korean probands with retinitis pigmentosa (RP39; 613809), Jung et al. (2023) identified compound heterozygosity for a c.2802T-G transversion in exon 13 of the USH2A gene, resulting in a cys934-to-trp (C934W) substitution within the LamE 8 domain, and another missense or truncating mutation in the USH2A gene (e.g., 608400.0017 and 608400.0018). Hearing tests were not performed, but no hearing problems were reported by any of the probands.

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

From Pangenia Genomics, Pangenia Inc., SCV003922396.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Asian	1	not provided	not provided	research	PubMed (1)
2	Asian	1	not provided	not provided	research	PubMed (1)

Description

The USH2A, c.2802T>G (p.Cys934Trp) variant is at extremely low frequency in population database; allele frequency in East Asia population is 0. 0025 by gnomAD v2.1.1. This variant is detected in trans with a pathogenic variant [USH2A, c.9570+1G>A] . This variant has been previously reported to be detected in numerous patients affected by retinitis pigmentosa or Usher syndrome as homozygote [PMID: 26338283], or in combination with another null variant in USH2A gene [PMID: 24938718, 25649381, 30948794, 33105608, 26338283], including frameshift and canonical splice sites variants (c.8368delT, c.8730dupT, c.9570+1G>A, c.99_100insT, c.5858-1G>A, c.5158delC, c.11811_11812delCT, c.12409delA, c.710delT). In at least 3 patients, the other null variant was confirmed to be in trans with this variant [PMID: 24938718, 30948794]. Multiple lines of computational evidence support a deleterious effect on the gene or gene product, REVEL = 0.849. This variant has been reported to co-segregate with retinitis pigmentosa or Usher syndrome in several families [PMID: 24938718, 26310143, 21686329].There are multiple submissions of this variant in ClinVar (Variation ID: 143179).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		1	not provided	not provided	not provided
2	unknown	no	not provided	not provided	not provided		1	not provided	not provided	not provided

From Baylor Genetics, SCV004207714.2

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

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

Last Updated: Oct 26, 2024

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