NM_206933.4(USH2A):c.12332C>T (p.Ser4111Phe) AND Retinitis pigmentosa 39

Germline classification:: Conflicting classifications of pathogenicity (3 submissions)
Last evaluated:: Mar 25, 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:: RCV001376289.6

Allele description [Variation Report for NM_206933.4(USH2A):c.12332C>T (p.Ser4111Phe)]

NM_206933.4(USH2A):c.12332C>T (p.Ser4111Phe)

Gene:

USH2A:usherin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q41

Genomic location:

Preferred name:

NM_206933.4(USH2A):c.12332C>T (p.Ser4111Phe)

HGVS:

NC_000001.11:g.215675579G>A
NG_009497.2:g.752870C>T
NM_206933.4:c.12332C>TMANE SELECT
NP_996816.3:p.Ser4111Phe
NC_000001.10:g.215848921G>A
NG_009497.1:g.752818C>T
NM_206933.2:c.12332C>T
NM_206933.3:c.12332C>T
c.12332C>T

Protein change:

S4111F

Links:

dbSNP: rs142095945

NCBI 1000 Genomes Browser:

rs142095945

Molecular consequence:

NM_206933.4:c.12332C>T - 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
SCV001573379	Ocular Genomics Institute, Massachusetts Eye and Ear	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Apr 8, 2021)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV004208178	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 25, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005087213	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jul 17, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 32037395, 33623043, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001573379

Ocular Genomics Institute, Massachusetts Eye and Ear

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Apr 8, 2021)

germline

research

PubMed (1)
[See all records that cite this PMID]

SCV004208178

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Mar 25, 2024)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV005087213

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jul 17, 2023)

germline

clinical testing

PubMed (3)
[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	research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Copy-number variation contributes 9% of pathogenicity in the inherited retinal degenerations.

Zampaglione E, Kinde B, Place EM, Navarro-Gomez D, Maher M, Jamshidi F, Nassiri S, Mazzone JA, Finn C, Schlegel D, Comander J, Pierce EA, Bujakowska KM.

Genet Med. 2020 Jun;22(6):1079-1087. doi: 10.1038/s41436-020-0759-8. Epub 2020 Feb 10.

PubMed [citation]

PMID:: 32037395
PMCID:: PMC7272325

Prioritizing variants of uncertain significance for reclassification using a rule-based algorithm in inherited retinal dystrophies.

Iancu IF, Avila-Fernandez A, Arteche A, Trujillo-Tiebas MJ, Riveiro-Alvarez R, Almoguera B, Martin-Merida I, Del Pozo-Valero M, Perea-Romero I, Corton M, Minguez P, Ayuso C.

NPJ Genom Med. 2021 Feb 23;6(1):18. doi: 10.1038/s41525-021-00182-z.

PubMed [citation]

PMID:: 33623043
PMCID:: PMC7902814

See all PubMed Citations (3)

Details of each submission

From Ocular Genomics Institute, Massachusetts Eye and Ear, SCV001573379.1

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

Description

The USH2A c.12332C>T variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2. Based on this evidence we have classified this variant as Variant of Uncertain Significance.

#	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 Baylor Genetics, SCV004208178.2

#	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

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV005087213.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Retinitis pigmentosa 39 (MIM#613809) and Usher syndrome, type 2A (MIM#276901). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to phenylalanine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (21 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported in two patients with inherited retinal dystrophy (PMID: 32037395, 33623043) and both classified as VUS. It has also been reported as VUS and pathogenic in ClinVar. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	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: Apr 7, 2025

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