NM_022370.4(ROBO3):c.1379A>G (p.Gln460Arg) AND Gaze palsy, familial horizontal, with progressive scoliosis 1

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Jan 9, 2021
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:: RCV000779048.8

Allele description [Variation Report for NM_022370.4(ROBO3):c.1379A>G (p.Gln460Arg)]

NM_022370.4(ROBO3):c.1379A>G (p.Gln460Arg)

Gene:

ROBO3:roundabout guidance receptor 3 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11q24.2

Genomic location:

Preferred name:

NM_022370.4(ROBO3):c.1379A>G (p.Gln460Arg)

HGVS:

NC_000011.10:g.124872932A>G
NG_016214.1:g.12524A>G
NM_022370.4:c.1379A>GMANE SELECT
NP_071765.2:p.Gln460Arg
NC_000011.9:g.124742828A>G
NM_022370.3:c.1379A>G

Protein change:

Q460R

Links:

dbSNP: rs771613910

NCBI 1000 Genomes Browser:

rs771613910

Molecular consequence:

NM_022370.4:c.1379A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Gaze palsy, familial horizontal, with progressive scoliosis 1 (HGPPS1)
Identifiers:: MONDO: MONDO:0020790; MedGen: C4551964; Orphanet: 2744; OMIM: 607313

Recent activity

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Homo sapiens zinc finger protein 197 (ZNF197), transcript variant 1, mRNA
Homo sapiens zinc finger protein 197 (ZNF197), transcript variant 1, mRNA
gi|1042818159|ref|NM_006991.4|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000915508	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Uncertain significance (Dec 17, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001468598	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 9, 2021)	germline	curation	PubMed (2) [See all records that cite these PMIDs] 18829051, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000915508

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 09 May 2019)

Uncertain significance
(Dec 17, 2018)

germline

clinical testing

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

Citation Link,

SCV001468598

Institute of Human Genetics, University of Leipzig Medical Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jan 9, 2021)

germline

curation

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	curation
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Five new consanguineous families with horizontal gaze palsy and progressive scoliosis and novel ROBO3 mutations.

Abu-Amero KK, al Dhalaan H, al Zayed Z, Hellani A, Bosley TM.

J Neurol Sci. 2009 Jan 15;276(1-2):22-6. doi: 10.1016/j.jns.2008.08.026. Epub 2008 Oct 1.

PubMed [citation]

PMID:: 18829051

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000915508.1

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

Description

The ROBO3 c.1379A>G (p.Gln460Arg) missense variant has been reported in one study in which it is identified in two siblings with familial horizontal gaze palsy with progressive scoliosis in a homozygous state (Abu-Amero et al. 2009). The parents and unaffected brother of the sisters were heterozygous for the variant. The p.Gln460Arg variant was absent from 170 healthy controls and is reported at a frequency of 0.000016 in the total population of the Genome Aggregation Database. Based on the evidence, the p.Gln460Arg variant is classified as a variant of unknown significance but suspicious for pathogenicity for familial horizontal gaze palsy with progressive scoliosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#	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 Institute of Human Genetics, University of Leipzig Medical Center, SCV001468598.1

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

Description

This ROBO3 variant was reported as Pathogenicâ€‹ in PMID: 18829051 with original nomenclature reported as c.1379A>G, Q460R. Variant was re-classified as Likely Pathogenic based on the criteria PM2_Supporting, PM3_Moderate, PP3_Supporting, PP4_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		not provided	not provided	not provided	not provided

Last Updated: Jun 23, 2024

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