VCV001342665.6 - ClinVar

NM_002941.4(ROBO1):c.4565C>T (p.Ser1522Leu)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(3)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Likely pathogenic(1); Likely benign(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_002941.4(ROBO1):c.4565C>T (p.Ser1522Leu)

Variation ID: 1342665 Accession: VCV001342665.6

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p12.3 3: 78606912 (GRCh38) [ NCBI UCSC ] 3: 78656062 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Aug 29, 2022	May 1, 2024	Oct 13, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_002941.4:c.4565C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_002932.1:p.Ser1522Leu	missense
NM_001145844.1:c.4430C>T	NP_001139316.1:p.Ser1477Leu	missense
NM_001145845.2:c.4265C>T	NP_001139317.1:p.Ser1422Leu	missense
NM_133631.4:c.4430C>T	NP_598334.2:p.Ser1477Leu	missense
NC_000003.12:g.78606912G>A
NC_000003.11:g.78656062G>A
NG_011729.1:g.1165998C>T

... more HGVS ... less HGVS

Protein change

S1422L, S1477L, S1522L

Other names

Canonical SPDI

NC_000003.12:78606911:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00060 (A)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 30x 0.00047

The Genome Aggregation Database (gnomAD) 0.00055

The Genome Aggregation Database (gnomAD), exomes 0.00059

1000 Genomes Project 0.00060

Exome Aggregation Consortium (ExAC) 0.00061

Trans-Omics for Precision Medicine (TOPMed) 0.00062

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00096

Links

OMIM: 602430.0009 dbSNP: rs199958211 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
ROBO1		No evidence available	No evidence available	GRCh38 GRCh37	469	482

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Likely benign (1)	criteria provided, single submitter	Oct 13, 2023	RCV002545227.3
Nystagmus, congenital, autosomal recessive	Pathogenic (1)	no assertion criteria provided	Apr 15, 2024	RCV003224893.3
Congenital nystagmus	Likely pathogenic (1)	criteria provided, single submitter	Feb 25, 2022	RCV002279766.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Feb 25, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Congenital nystagmus Affected status: yes Allele origin: germline	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine Accession: SCV002099445.1 First in ClinVar: Aug 29, 2022 Last updated: Aug 29, 2022	Clinical Features: Congenital nystagmus (present) Family history: yes
Likely benign (Oct 13, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003293435.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024
Pathogenic (Apr 15, 2024)	no assertion criteria provided Method: literature only	NYSTAGMUS 8, CONGENITAL, AUTOSOMAL RECESSIVE (1 family) Affected status: not provided Allele origin: germline	OMIM Accession: SCV003853331.4 First in ClinVar: Apr 09, 2023 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 35348658 Comment on evidence: In 3 adult brothers, born of consanguineous Turkish parents (family 1, HOU2644), with autosomal recessive congenital nystagmus-8 (NYS8; 257400), Huang et al. (2022) identified a … (more) In 3 adult brothers, born of consanguineous Turkish parents (family 1, HOU2644), with autosomal recessive congenital nystagmus-8 (NYS8; 257400), Huang et al. (2022) identified a homozygous c.4565C-T transition (c.4565C-T, NM_002941) in the ROBO1 gene, resulting in a ser1522-to-leu (S1522L) substitution in the C-terminal cytoplasmic domain. The mutation, which was found by exome sequencing, segregated with the disorder in the family. It was found in the gnomAD database in heterozygous state at a frequency of 0.058% and once in the homozygous state in an individual of African origin. The authors noted that this mild phenotype may have been overlooked or that the variant may show incomplete penetrance. Studies in Drosophila suggested that the S1522L variant is a partial loss-of-function allele, as it was not as toxic as human wildtype ROBO1. The patients had no additional neurologic features and brain imaging was normal. (less)

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Novel dominant and recessive variants in human ROBO1 cause distinct neurodevelopmental defects through different mechanisms.	Huang Y	Human molecular genetics	2022	PMID: 35348658

Text-mined citations for rs199958211 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_002941.4(ROBO1):c.4565C>T (p.Ser1522Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs199958211 ...