NM_014249.4(NR2E3):c.131C>T (p.Ser44Leu) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Oct 25, 2022
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:: RCV000488991.3

Allele description [Variation Report for NM_014249.4(NR2E3):c.131C>T (p.Ser44Leu)]

NM_014249.4(NR2E3):c.131C>T (p.Ser44Leu)

Gene:

NR2E3:nuclear receptor subfamily 2 group E member 3 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

15q23

Genomic location:

Preferred name:

NM_014249.4(NR2E3):c.131C>T (p.Ser44Leu)

HGVS:

NC_000015.10:g.71811495C>T
NG_009113.2:g.5941C>T
NM_014249.4:c.131C>TMANE SELECT
NM_016346.4:c.131C>T
NP_055064.1:p.Ser44Leu
NP_057430.1:p.Ser44Leu
NC_000015.9:g.72103835C>T
NM_014249.2:c.131C>T
NM_014249.3:c.131C>T

Protein change:

S44L

Links:

dbSNP: rs202098481

NCBI 1000 Genomes Browser:

rs202098481

Molecular consequence:

NM_014249.4:c.131C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_016346.4:c.131C>T - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000576886	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Uncertain significance (Apr 17, 2017)	germline	clinical testing	Citation Link,
SCV001216190	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 25, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 18294254, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000576886

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Uncertain significance
(Apr 17, 2017)

germline

clinical testing

Citation Link,

SCV001216190

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 25, 2022)

germline

clinical testing

PubMed (2)
[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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Analysis of the involvement of the NR2E3 gene in autosomal recessive retinal dystrophies.

Bernal S, Solans T, Gamundi MJ, Hernan I, de Jorge L, Carballo M, Navarro R, Tizzano E, Ayuso C, Baiget M.

Clin Genet. 2008 Apr;73(4):360-6. doi: 10.1111/j.1399-0004.2008.00963.x. Epub 2008 Feb 20.

PubMed [citation]

PMID:: 18294254

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From GeneDx, SCV000576886.4

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

Description

The S44L variant in the NR2E3 gene has been reported previously in an individual with autosomal recessive retinitis pigmentosa, however, this variant did not segregate with the disease in the family (Bernal et al., 2008). The S44L variant is observed in 1/532 (0.1%) alleles from individuals of Latino background in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The S44L variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret S44L as a 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 Invitae, SCV001216190.2

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

Description

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 44 of the NR2E3 protein (p.Ser44Leu). This variant is present in population databases (rs202098481, gnomAD 0.05%). This missense change has been observed in individual(s) with retinitis pigmentosa (PMID: 18294254). ClinVar contains an entry for this variant (Variation ID: 426441). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NR2E3 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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: Mar 16, 2024

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