VCV000917896.4 - ClinVar

NM_001378974.1(FBXW11):c.1150C>T (p.Arg384Trp)

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); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001378974.1(FBXW11):c.1150C>T (p.Arg384Trp)

Variation ID: 917896 Accession: VCV000917896.4

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 5q35.1 5: 171876356 (GRCh38) [ NCBI UCSC ] 5: 171303360 (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	Jun 22, 2020	Dec 24, 2023	Sep 2, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001378974.1:c.1150C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001365903.1:p.Arg384Trp	missense
NM_001378975.1:c.1081C>T	NP_001365904.1:p.Arg361Trp	missense
NM_001378976.1:c.1054C>T	NP_001365905.1:p.Arg352Trp	missense
NM_001378977.1:c.991C>T	NP_001365906.1:p.Arg331Trp	missense
NM_001378978.1:c.991C>T	NP_001365907.1:p.Arg331Trp	missense
NM_001378979.1:c.991C>T	NP_001365908.1:p.Arg331Trp	missense
NM_001378980.1:c.985C>T	NP_001365909.1:p.Arg329Trp	missense
NM_012300.3:c.1087C>T	NP_036432.2:p.Arg363Trp	missense
NM_033644.3:c.1048C>T	NP_387448.2:p.Arg350Trp	missense
NM_033645.3:c.985C>T	NP_387449.2:p.Arg329Trp	missense
NC_000005.10:g.171876356G>A
NC_000005.9:g.171303360G>A
NG_009275.2:g.135518C>T

... more HGVS ... less HGVS

Protein change

R363W, R329W, R331W, R350W, R352W, R361W, R384W

Other names

Canonical SPDI

NC_000005.10:171876355: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.

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

Links

OMIM: 605651.0001 dbSNP: rs1758081729 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.
FBXW11		No evidence available	Little evidence for dosage pathogenicity	GRCh38 GRCh37	83	103

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.
Neurodevelopmental, jaw, eye, and digital syndrome	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	Sep 2, 2023	RCV001175172.5

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 (Apr 13, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Neurodevelopmental, jaw, eye, and digital syndrome Affected status: unknown Allele origin: unknown	SIB Swiss Institute of Bioinformatics Accession: SCV001571396.1 First in ClinVar: Apr 18, 2021 Last updated: Apr 18, 2021	Publications: PubMed (1) PubMed: 31402090 Comment: This variant is interpreted as likely pathogenic for Neurodevelopmental, jaw, eye, and digital syndrome, autosomal dominant. The following ACMG Tag(s) were applied: Absent from controls … (more) This variant is interpreted as likely pathogenic for Neurodevelopmental, jaw, eye, and digital syndrome, autosomal dominant. The following ACMG Tag(s) were applied: Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium (PM2); De novo (paternity and maternity confirmed) (PS2 downgraded to moderate); Multiple lines of computational evidence support a deleterious effect on the gene or gene product (PP3); Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease (PP2). (less)
Uncertain significance (Sep 02, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neurodevelopmental, jaw, eye, and digital syndrome Affected status: unknown Allele origin: germline	Clinical Genomics Laboratory, Washington University in St. Louis Accession: SCV004176994.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023	Comment: The FBXW11 c.1150C>T (p.Arg384Trp) variant has been reported in the medical literature in a de novo state in an individual with striking eye anomalies, digital … (more) The FBXW11 c.1150C>T (p.Arg384Trp) variant has been reported in the medical literature in a de novo state in an individual with striking eye anomalies, digital anomalies, and psychiatric issues (Holt RJ et al., PMID: 31402090). This variant is absent from the general population (gnomAD v.2.1.1), indicating it is not a common variant. Computational predictors are uncertain/conflicting as to the impact of this variant on FBXW11 protein function. This variant has been submitted to ClinVar as likely pathogenic by one laboratory (variation ID: 917896). Due to limited information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of this variant is uncertain at this time. (less)
Pathogenic (Jun 16, 2020)	no assertion criteria provided Method: literature only	NEURODEVELOPMENTAL, JAW, EYE, AND DIGITAL SYNDROME Affected status: not provided Allele origin: germline	OMIM Accession: SCV001338771.1 First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020	Publications: PubMed (1) PubMed: 31402090 Comment on evidence: In a 24-year-old woman (individual 1) with neurodevelopmental, jaw, eye, and digital syndrome (NEDJED; 618914), Holt et al. (2019) identified heterozygosity for a de novo … (more) In a 24-year-old woman (individual 1) with neurodevelopmental, jaw, eye, and digital syndrome (NEDJED; 618914), Holt et al. (2019) identified heterozygosity for a de novo c.1087C-T transition (c.1087C-T, NM_012300.2) in exon 13 of the FBXW11 gene, resulting in an arg363-to-trp (R363W) substitution at a highly conserved residue at the N-terminal end of the WD4 repeat within the WD40 domain. The mutation was not found in the gnomAD database. (less)

Comment:

This variant is interpreted as likely pathogenic for Neurodevelopmental, jaw, eye, and digital syndrome, autosomal dominant. The following ACMG Tag(s) were applied: Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium (PM2); De novo (paternity and maternity confirmed) (PS2 downgraded to moderate); Multiple lines of computational evidence support a deleterious effect on the gene or gene product (PP3); Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease (PP2).

Comment:

The FBXW11 c.1150C>T (p.Arg384Trp) variant has been reported in the medical literature in a de novo state in an individual with striking eye anomalies, digital anomalies, and psychiatric issues (Holt RJ et al., PMID: 31402090). This variant is absent from the general population (gnomAD v.2.1.1), indicating it is not a common variant. Computational predictors are uncertain/conflicting as to the impact of this variant on FBXW11 protein function. This variant has been submitted to ClinVar as likely pathogenic by one laboratory (variation ID: 917896). Due to limited information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of this variant is uncertain at this time.

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
De Novo Missense Variants in FBXW11 Cause Diverse Developmental Phenotypes Including Brain, Eye, and Digit Anomalies.	Holt RJ	American journal of human genetics	2019	PMID: 31402090

Text-mined citations for rs1758081729 ...

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 Feb 04, 2024

ClinVar Genomic variation as it relates to human health

NM_001378974.1(FBXW11):c.1150C>T (p.Arg384Trp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1758081729 ...