NM_000266.4(NDP):c.269G>A (p.Arg90His) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Apr 22, 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:: RCV001306511.13

Allele description [Variation Report for NM_000266.4(NDP):c.269G>A (p.Arg90His)]

NM_000266.4(NDP):c.269G>A (p.Arg90His)

Genes:

NDP-AS1:NDP antisense RNA 1 [Gene - HGNC]
NDP:norrin cystine knot growth factor NDP [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xp11.3

Genomic location:

Preferred name:

NM_000266.4(NDP):c.269G>A (p.Arg90His)

HGVS:

NC_000023.11:g.43949932C>T
NG_009832.1:g.28744G>A
NM_000266.4:c.269G>AMANE SELECT
NP_000257.1:p.Arg90His
NC_000023.10:g.43809178C>T
NM_000266.3:c.269G>A
NR_046631.1:n.201C>T

Protein change:

R90H

Links:

dbSNP: rs104894867

NCBI 1000 Genomes Browser:

rs104894867

Molecular consequence:

NM_000266.4:c.269G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_046631.1:n.201C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

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
SCV001495886	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Apr 22, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 14635119, 31456290, 28492532
SCV001760757	Laboratoire Génétique Moléculaire, CHRU TOURS	criteria provided, single submitter (ACMG Guidelines, 2015)	Benign (Jun 4, 2019)	maternal	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002504561	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely benign (Oct 31, 2019)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001495886

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Apr 22, 2023)

germline

clinical testing

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

SCV001760757

Laboratoire Génétique Moléculaire, CHRU TOURS

criteria provided, single submitter

(ACMG Guidelines, 2015)

Benign
(Jun 4, 2019)

maternal

clinical testing

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

SCV002504561

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely benign
(Oct 31, 2019)

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	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
not provided	maternal	no	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

NDP gene mutations in 14 French families with Norrie disease.

Royer G, Hanein S, Raclin V, Gigarel N, Rozet JM, Munnich A, Steffann J, Dufier JL, Kaplan J, Bonnefont JP.

Hum Mutat. 2003 Dec;22(6):499.

PubMed [citation]

PMID:: 14635119

A nationwide genetic analysis of inherited retinal diseases in Israel as assessed by the Israeli inherited retinal disease consortium (IIRDC).

Sharon D, Ben-Yosef T, Goldenberg-Cohen N, Pras E, Gradstein L, Soudry S, Mezer E, Zur D, Abbasi AH, Zeitz C, Cremers FPM, Khan MI, Levy J, Rotenstreich Y, Birk OS, Ehrenberg M, Leibu R, Newman H, Shomron N, Banin E, Perlman I.

Hum Mutat. 2020 Jan;41(1):140-149. doi: 10.1002/humu.23903. Epub 2019 Sep 15.

PubMed [citation]

PMID:: 31456290

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001495886.4

#	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 replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 90 of the NDP protein (p.Arg90His). 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. This variant disrupts the p.Arg90 amino acid residue in NDP. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14635119). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NDP protein function. ClinVar contains an entry for this variant (Variation ID: 812352). This missense change has been observed in individual(s) with Norrie disease (PMID: 31456290). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database.

#	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 Laboratoire Génétique Moléculaire, CHRU TOURS, SCV001760757.1

#	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	maternal	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneDx, SCV002504561.2

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

Description

See Variant Classification Assertion Criteria.

#	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: Sep 29, 2024

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