NM_206933.4(USH2A):c.4124C>T (p.Ser1375Leu) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Nov 5, 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:: RCV001365783.11

Allele description [Variation Report for NM_206933.4(USH2A):c.4124C>T (p.Ser1375Leu)]

NM_206933.4(USH2A):c.4124C>T (p.Ser1375Leu)

Genes:

USH2A-AS1:USH2A antisense RNA 1 [Gene - HGNC]
USH2A:usherin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q41

Genomic location:

Preferred name:

NM_206933.4(USH2A):c.4124C>T (p.Ser1375Leu)

HGVS:

NC_000001.11:g.216196680G>A
NG_009497.2:g.231769C>T
NM_007123.6:c.4124C>T
NM_206933.4:c.4124C>TMANE SELECT
NP_009054.6:p.Ser1375Leu
NP_996816.3:p.Ser1375Leu
NC_000001.10:g.216370022G>A
NG_009497.1:g.231717C>T
NM_206933.2:c.4124C>T

Protein change:

S1375L

Links:

dbSNP: rs751479180

NCBI 1000 Genomes Browser:

rs751479180

Molecular consequence:

NM_007123.6:c.4124C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_206933.4:c.4124C>T - missense variant - [Sequence Ontology: SO:0001583]

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
SCV001562065	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 5, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 25425308, 32188678, 34781295, 28492532
SCV001789625	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Mar 13, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001562065

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 5, 2024)

germline

clinical testing

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

SCV001789625

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely pathogenic
(Mar 13, 2023)

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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Cone responses in Usher syndrome types 1 and 2 by microvolt electroretinography.

Zein WM, Falsini B, Tsilou ET, Turriff AE, Schultz JM, Friedman TB, Brewer CC, Zalewski CK, King KA, Muskett JA, Rehman AU, Morell RJ, Griffith AJ, Sieving PA.

Invest Ophthalmol Vis Sci. 2014 Nov 25;56(1):107-14. doi: 10.1167/iovs.14-15355.

PubMed [citation]

PMID:: 25425308
PMCID:: PMC4288141

Prevalence and genetic-phenotypic characteristics of patients with USH2A mutations in a large cohort of Chinese patients with inherited retinal disease.

Gao FJ, Wang DD, Chen F, Sun HX, Hu FY, Xu P, Li J, Liu W, Qi YH, Li W, Wang M, Zhang S, Xu GZ, Chang Q, Wu JH.

Br J Ophthalmol. 2021 Jan;105(1):87-92. doi: 10.1136/bjophthalmol-2020-315878. Epub 2020 Mar 18.

PubMed [citation]

PMID:: 32188678
PMCID:: PMC7788223

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001562065.5

#	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 replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 1375 of the USH2A protein (p.Ser1375Leu). This variant is present in population databases (rs751479180, gnomAD 0.0009%). This missense change has been observed in individual(s) with retinitis pigmentosa (PMID: 25425308, 32188678, 34781295; internal data). 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: 1056888). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt USH2A protein function with a negative predictive value of 95%. 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, SCV001789625.2

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

Description

Observed with a second variant (phase unknown) in unrelated patients with retinitis pigmentosa in the published literature (Colombo et al., 2018; Gao et al., 2020); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25425308, 29940899, 31054281, 34781295, 32188678)

#	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: May 16, 2025

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