VCV000069961.3 - ClinVar

NM_001349798.2(FBXW7):c.1513C>T (p.Arg505Cys)

Germline

Classification

criteria provided, single submitter. Learn more about how ClinVar calculates review status.

Likely pathogenic
Likely pathogenic (1)

This classification is based on the single submission received

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.

Somatic

Clinical impact

criteria provided, single submitter. Learn more about how ClinVar calculates review status.

Tier I (Strong) for Embryonal rhabdomyosarcoma

+lower levels of evidence for 4 other tumor types

1 out of 5 submissions contributed to this classification

The aggregate somatic clinical impact for this variant for one or more tumor types, using the AMP/ASCO/CAP terminology. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001349798.2(FBXW7):c.1513C>T (p.Arg505Cys)

Variation ID: 69961 Accession: VCV000069961.3

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 4q31.3 4: 152326137 (GRCh38) [ NCBI UCSC ] 4: 153247289 (GRCh37) [ NCBI UCSC ] 4: 153466739 (NCBI36) [ 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	Mar 8, 2017	Oct 21, 2023
Somatic - Clinical impact	Nov 22, 2025	Nov 22, 2025	Oct 8, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_001349798.2:c.1513C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001336727.1:p.Arg505Cys	missense
NM_001013415.2:c.1159C>T	NP_001013433.1:p.Arg387Cys	missense
NM_018315.5:c.1273C>T	NP_060785.2:p.Arg425Cys	missense
NM_033632.3:c.1513C>T	NP_361014.1:p.Arg505Cys	missense
NC_000004.12:g.152326137G>A
NC_000004.11:g.153247289G>A
NG_029466.2:g.215737C>T
LRG_1141:g.215737C>T
LRG_1141t1:c.1513C>T	LRG_1141p1:p.Arg505Cys
LRG_1141t2:c.1273C>T	LRG_1141p2:p.Arg425Cys
LRG_1141t3:c.1159C>T	LRG_1141p3:p.Arg387Cys

... more HGVS ... less HGVS

Protein change

R505C, R387C, R425C

Other names

Canonical SPDI

NC_000004.12:152326136:G:A

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.

The Genome Aggregation Database (gnomAD), exomes 0.00000

Links

ClinGen: CA16602253 dbSNP: rs149680468 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.
FBXW7		-	-	GRCh38 GRCh37	280	328

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.
FBXW7-related neurodevelopmental disorder	Likely pathogenic (1)	criteria provided, single submitter	-	RCV003335089.1

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.	Expand all rows Collapse all rows 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 (-) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	FBXW7-related neurodevelopmental disorder	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego Accession: SCV004046385.1 First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023	Comment: show This variant has not been previously reported or functionally characterized in the literature to our knowledge. A different amino acid change at the same residue (p.Arg505His) has been previously reported in an individual with FBXW7-related disorder (PMID: 35395208). The c.1513C>T (p.Arg505Cys) variant is absent from the gnomAD population database and thus is presumed to be rare. The c.1513C>T (p.Arg505Cys) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.1513C>T (p.Arg505Cys) variant is classified as Likely Pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Comment:

Variant has Tier II (potential) clinical significance as a diagnostic inclusion criterion in medulloblastoma non-WNT/non-SHH group 3, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Information in the literature supports potential biologic effect of variant (PMIDs: 24838835, 30510140). 3) Diagnostic significance based on multiple small studies (Evidence Level C; PMIDs: 28726821, 33502920, 33741928).

Comment:

This variant has not been previously reported or functionally characterized in the literature to our knowledge. A different amino acid change at the same residue (p.Arg505His) has been previously reported in an individual with FBXW7-related disorder (PMID: 35395208). The c.1513C>T (p.Arg505Cys) variant is absent from the gnomAD population database and thus is presumed to be rare. The c.1513C>T (p.Arg505Cys) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.1513C>T (p.Arg505Cys) variant is classified as Likely Pathogenic.

Comment:

Variant has Tier II (potential) clinical significance as a diagnostic inclusion criterion in alveolar rhabdomyosarcoma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMIDs: 24838835, 30510140). 4) Diagnostic significance based on multiple small studies (Evidence Level C).

Comment:

Variant has Tier II (potential) clinical significance as a diagnostic inclusion criterion in medulloblastoma WNT activated, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Information in the literature supports potential biologic effect of variant (PMIDs: 24838835, 30510140). 3) Diagnostic significance based on multiple small studies (Evidence Level C; PMIDs: 28726821, 33502920).

Comment:

Variant has Tier II (potential) clinical significance as a diagnostic inclusion criterion in diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Information in the literature supports potential biologic effect of variant (PMIDs: 24838835, 30510140). 3) Assists in diagnosis alone or along with other biomarkers based on small studies or few case reports (Evidence Level D; PMID: 28966033).

Comment:

Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in embryonal rhabdomyosarcoma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMIDs: 24838835, 30510140, 38483988). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 24436047, 34166060, 25768946).

Citations for germline classification of this variant

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Conditions - Somatic

Tumor type Help The tumor type for this variant-condition (RCV) record in ClinVar.	Clinical impact (# of submissions) Help The aggregate somatic clinical impact for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate somatic clinical impact is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the tumor type.	Variation/condition record Help The most recent date that a submitter evaluated this variant for the tumor type.
Medulloblastoma WNT activated	Tier II (Potential) - diagnostic - supports diagnosis (1)	May 25, 2023	RCV006253765.1
Medulloblastoma non-WNT/non-SHH group 3	Tier II (Potential) - diagnostic - supports diagnosis (1)	Oct 31, 2025	RCV006253766.1
Embryonal rhabdomyosarcoma	Tier I (Strong) - diagnostic - supports diagnosis (1)	Oct 8, 2025	RCV006253763.1
Diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype	Tier II (Potential) - diagnostic - supports diagnosis (1)	Nov 10, 2023	RCV006253764.1
Alveolar rhabdomyosarcoma	Tier II (Potential) - diagnostic - supports diagnosis (1)	May 8, 2023	RCV006253762.1

Submissions - Somatic

Clinical impact Help The submitted somatic clinical impact 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)	Tumor type Help The tumor type 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.	Expand all rows Help This column includes more information supporting the somatic clinical impact, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.

Tier I (Strong) - Diagnostic - supports diagnosis (Oct 08, 2025) C Contributing to aggregate classification	criteria provided, single submitter (AMP/ASCO/CAP Guidelines, 2017)	Embryonal rhabdomyosarcoma	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital Accession: SCV007105735.1 First In ClinVar: Nov 22, 2025 Last updated: Nov 22, 2025	Publications: PubMed (6) PubMed: 24436047‚ 24838835‚ 25768946‚ 30510140‚ 34166060‚ 38483988 Comment: show Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in embryonal rhabdomyosarcoma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMIDs: 24838835, 30510140, 38483988). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 24436047, 34166060, 25768946). (less) Observation: 1 Collection method: clinical testing Allele origin: somatic Affected status: yes Observation 1 Collection method: clinical testing Allele origin: somatic Affected status: yes

Tier II (Potential) - Diagnostic - supports diagnosis (Oct 31, 2025) N Not contributing to aggregate classification	criteria provided, single submitter (AMP/ASCO/CAP Guidelines, 2017)	Medulloblastoma non-WNT/non-SHH group 3	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital Accession: SCV007105522.1 First In ClinVar: Nov 22, 2025 Last updated: Nov 22, 2025	Publications: PubMed (5) PubMed: 24838835‚ 28726821‚ 30510140‚ 33502920‚ 33741928 Comment: show Variant has Tier II (potential) clinical significance as a diagnostic inclusion criterion in medulloblastoma non-WNT/non-SHH group 3, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Information in the literature supports potential biologic effect of variant (PMIDs: 24838835, 30510140). 3) Diagnostic significance based on multiple small studies (Evidence Level C; PMIDs: 28726821, 33502920, 33741928). (less) Observation: 1 Collection method: clinical testing Allele origin: somatic Affected status: yes Observation 1 Collection method: clinical testing Allele origin: somatic Affected status: yes

Tier II (Potential) - Diagnostic - supports diagnosis (May 08, 2023) N Not contributing to aggregate classification	criteria provided, single submitter (AMP/ASCO/CAP Guidelines, 2017)	Alveolar rhabdomyosarcoma	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital Accession: SCV007105471.1 First In ClinVar: Nov 22, 2025 Last updated: Nov 22, 2025	Publications: PubMed (2) PubMed: 24838835‚ 30510140 Comment: show Variant has Tier II (potential) clinical significance as a diagnostic inclusion criterion in alveolar rhabdomyosarcoma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMIDs: 24838835, 30510140). 4) Diagnostic significance based on multiple small studies (Evidence Level C). (less) Observation: 1 Collection method: clinical testing Allele origin: somatic Affected status: yes Observation 1 Collection method: clinical testing Allele origin: somatic Affected status: yes

Tier II (Potential) - Diagnostic - supports diagnosis (May 25, 2023) N Not contributing to aggregate classification	criteria provided, single submitter (AMP/ASCO/CAP Guidelines, 2017)	Medulloblastoma WNT activated	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital Accession: SCV007105472.1 First In ClinVar: Nov 22, 2025 Last updated: Nov 22, 2025	Publications: PubMed (4) PubMed: 24838835‚ 28726821‚ 30510140‚ 33502920 Comment: show Variant has Tier II (potential) clinical significance as a diagnostic inclusion criterion in medulloblastoma WNT activated, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Information in the literature supports potential biologic effect of variant (PMIDs: 24838835, 30510140). 3) Diagnostic significance based on multiple small studies (Evidence Level C; PMIDs: 28726821, 33502920). (less) Observation: 1 Collection method: clinical testing Allele origin: somatic Affected status: yes Observation 1 Collection method: clinical testing Allele origin: somatic Affected status: yes

Tier II (Potential) - Diagnostic - supports diagnosis (Nov 10, 2023) N Not contributing to aggregate classification	criteria provided, single submitter (AMP/ASCO/CAP Guidelines, 2017)	Diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital Accession: SCV007105723.1 First In ClinVar: Nov 22, 2025 Last updated: Nov 22, 2025	Publications: PubMed (3) PubMed: 24838835‚ 28966033‚ 30510140 Comment: show Variant has Tier II (potential) clinical significance as a diagnostic inclusion criterion in diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Information in the literature supports potential biologic effect of variant (PMIDs: 24838835, 30510140). 3) Assists in diagnosis alone or along with other biomarkers based on small studies or few case reports (Evidence Level D; PMID: 28966033). (less) Observation: 1 Collection method: clinical testing Allele origin: somatic Affected status: yes Observation 1 Collection method: clinical testing Allele origin: somatic Affected status: yes

Comment:

Citations for somatic classification of this variant

Title	Author	Journal	Year	Link
Epidermal growth factor receptor (EGFR) is a target of the tumor-suppressor E3 ligase FBXW7.	Boretto M	Proceedings of the National Academy of Sciences of the United States of America	2024	PMID: 38483988
Genomic Classification and Clinical Outcome in Rhabdomyosarcoma: A Report From an International Consortium.	Shern JF	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2021	PMID: 34166060
The transcriptional landscape of Shh medulloblastoma.	Skowron P	Nature communications	2021	PMID: 33741928
Clinical Outcomes and Patient-Matched Molecular Composition of Relapsed Medulloblastoma.	Kumar R	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2021	PMID: 33502920
FBXW7 mutations reduce binding of NOTCH1, leading to cleaved NOTCH1 accumulation and target gene activation in CLL.	Close V	Blood	2019	PMID: 30510140
Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma.	Mackay A	Cancer cell	2017	PMID: 28966033
The whole-genome landscape of medulloblastoma subtypes.	Northcott PA	Nature	2017	PMID: 28726821
Clonality and evolutionary history of rhabdomyosarcoma.	Chen L	PLoS genetics	2015	PMID: 25768946
FBXW7 mutations in melanoma and a new therapeutic paradigm.	Aydin IT	Journal of the National Cancer Institute	2014	PMID: 24838835
Comprehensive genomic analysis of rhabdomyosarcoma reveals a landscape of alterations affecting a common genetic axis in fusion-positive and fusion-negative tumors.	Shern JF	Cancer discovery	2014	PMID: 24436047

Text-mined citations for rs149680468 ...

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 Dec 01, 2025