NM_001354768.3(NRL):c.544C>T (p.Gln182Ter) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Nov 1, 2023
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:: RCV000760699.12

Allele description [Variation Report for NM_001354768.3(NRL):c.544C>T (p.Gln182Ter)]

NM_001354768.3(NRL):c.544C>T (p.Gln182Ter)

Genes:

LOC130055387:ATAC-STARR-seq lymphoblastoid silent region 5620 [Gene]
NRL:neural retina leucine zipper [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

14q11.2

Genomic location:

Preferred name:

NM_001354768.3(NRL):c.544C>T (p.Gln182Ter)

HGVS:

NC_000014.9:g.24081406G>A
NG_011697.2:g.38609C>T
NM_001354768.3:c.544C>TMANE SELECT
NM_001354769.1:c.544C>T
NM_001354770.2:c.229C>T
NM_006177.5:c.544C>T
NP_001341697.1:p.Gln182Ter
NP_001341698.1:p.Gln182Ter
NP_001341699.1:p.Gln77Ter
NP_006168.1:p.Gln182Ter
NC_000014.8:g.24550615G>A
NM_006177.3:c.544C>T
NM_006177.5:c.[544C>T]

Protein change:

Q182*

Links:

dbSNP: rs901811301

NCBI 1000 Genomes Browser:

rs901811301

Molecular consequence:

NM_001354768.3:c.544C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354769.1:c.544C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354770.2:c.229C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_006177.5:c.544C>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

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Arabidopsis thaliana Protein kinase superfamily protein (AT1G78530), mRNA
Arabidopsis thaliana Protein kinase superfamily protein (AT1G78530), mRNA
gi|1063693329|ref|NM_106500.3|

Nucleotide
xv54f07.x1 NCI_CGAP_Lu28 Homo sapiens cDNA clone IMAGE:2816965 3', mRNA sequence
xv54f07.x1 NCI_CGAP_Lu28 Homo sapiens cDNA clone IMAGE:2816965 3', mRNA sequence
gi|6656656|gnl|dbEST|3652727|gb|AW2 .1|

Nucleotide
pemB [Dickeya dadantii 3937]
pemB [Dickeya dadantii 3937]
Gene ID:9733317

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000890591	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Pathogenic (Sep 11, 2018)	germline	clinical testing	Citation Link,
SCV002315469	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 17, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 35693422, 29385733, 28492532
SCV004184392	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Likely pathogenic (Nov 1, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000890591

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Pathogenic
(Sep 11, 2018)

germline

clinical testing

Citation Link,

SCV002315469

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 17, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV004184392

CeGaT Center for Human Genetics Tuebingen

criteria provided, single submitter

(CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)

Likely pathogenic
(Nov 1, 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	yes	1	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

Novel homozygous mutations in the transcription factor NRL cause non-syndromic retinitis pigmentosa.

El-Asrag ME, Corton M, McKibbin M, Avila-Fernandez A, Mohamed MD, Blanco-Kelly F, Toomes C, Inglehearn CF, Ayuso C, Ali M.

Mol Vis. 2022;28:48-56.

PubMed [citation]

PMID:: 35693422
PMCID:: PMC9122474

Autosomal Recessive NRL Mutations in Patients with Enhanced S-Cone Syndrome.

Littink KW, Stappers PTY, Riemslag FCC, Talsma HE, van Genderen MM, Cremers FPM, Collin RWJ, van den Born LI.

Genes (Basel). 2018 Jan 30;9(2). doi:pii: E68. 10.3390/genes9020068. Erratum in: Genes (Basel). 2018 Mar 07;9(3):E145. doi: 10.3390/genes9030145.

PubMed [citation]

PMID:: 29385733
PMCID:: PMC5852564

See all PubMed Citations (3)

Details of each submission

From GeneDx, SCV000890591.1

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

Description

The Q182X variant in the NRL gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The Q182X variant is not observed in large population cohorts (Lek et al., 2016). We interpret Q182X as a pathogenic variant.

#	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, SCV002315469.3

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

Description

This sequence change creates a premature translational stop signal (p.Gln182*) in the NRL gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 56 amino acid(s) of the NRL protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with retinitis pigmentosa (PMID: 35693422). ClinVar contains an entry for this variant (Variation ID: 620329). This variant disrupts the C-terminus of the NRL protein. Other variant(s) that disrupt this region (p.Cys219Valfs*4) have been observed in individuals with NRL-related conditions (PMID: 29385733). This suggests that this may be a clinically significant region of the protein. 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

From CeGaT Center for Human Genetics Tuebingen, SCV004184392.7

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

Description

NRL: PVS1:Strong, PM2, PM3:Supporting

#	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		1	not provided	not provided	not provided

Last Updated: Aug 4, 2024

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